Antagonists of the vanilloid receptor subtype 1 (vr1) and use thereof

ABSTRACT

The present invention is directed to compounds of formula (I) 
     
       
         
         
             
             
         
       
     
     wherein variables W, X, Y, D, A, n, R 1 , R 2  and R 9  are as defined in the description.

This application is a Continuation of U.S. patent application Ser. No.12/365,643 filed on Feb. 4, 2009, which is a Divisional of U.S. patentapplication Ser. No. 11/431,459 filed on May 10, 2006, and is now U.S.Pat. No. 7,504,520 that issued on Mar. 17, 2009, which claims priorityto U.S. patent application Ser. No. 60/679,708 filed May 11, 2005, allof which are incorporated herein by reference in their entirety.

FIELD OF INVENTION

The present invention relates to compounds of formula (I), which areuseful for treating disorders caused by or exacerbated by vanilloidreceptor activity. The present invention also includes pharmaceuticalcompositions containing compounds of formula (I) and methods fortreating pain, bladder overactivity, and urinary incontinence using saidcompounds and said pharmaceutical compositions.

BACKGROUND OF INVENTION

Nociceptors are primary sensory afferent (C and Aδ fibers) neurons thatare activated by a wide variety of noxious stimuli including chemical,mechanical, thermal, and proton (pH<6) modalities. The lipophillicvanilloid, capsaicin, activates primary sensory fibers via a specificcell surface capsaicin receptor, cloned as VR1. The intradermaladministration of capsaicin is characterized by an initial burning orhot sensation followed by a prolonged period of analgesia. The analgesiccomponent of VR1 receptor activation is thought to be mediated by acapsaicin-induced desensitization of the primary sensory afferentterminal. Thus, the long lasting anti-nociceptive effects of capsaicinhas prompted the clinical use of capsaicin analogs as analgesic agents.Further, capsazepine, a capsaicin receptor antagonist can reduceinflammation-induced hyperalgesia in animal models. VR1 receptors arealso localized on sensory afferents which innervate the bladder.Capsaicin or resiniferatoxin has been shown to ameliorate incontinencesymptoms upon injection into the bladder.

The VR1 receptor has been called a “polymodal detector” of noxiousstimuli since it can be activated in several ways. The receptor channelis activated by capsaicin and other vanilloids and thus is classified asa ligand-gated ion channel. VR1 receptor activation by capsaicin can beblocked by the competitive VR1 receptor antagonist, capsazepine. Thechannel can also be activated by protons. Under mildly acidic conditions(pH 6-7), the affinity of capsaicin for the receptor is increased,whereas at pH<6, direct activation of the channel occurs. In addition,when membrane temperature reaches 43° C., the channel is opened. Thusheat can directly gate the channel in the absence of ligand. Thecapsaicin analog, capsazepine, which is a competitive antagonist ofcapsaicin, blocks activation of the channel in response to capsaicin,acid, or heat.

The channel is a nonspecific cation conductor. Both extracellular sodiumand calcium enter through the channel pore, resulting in cell membranedepolarization. This depolarization increases neuronal excitability,leading to action potential firing and transmission of a noxious nerveimpulse to the spinal cord. In addition, depolarization of theperipheral terminal can lead to release of inflammatory peptides suchas, but not limited to, substance P and CGRP, leading to enhancedperipheral sensitization of tissue.

Recently, two groups have reported the generation of a “knock-out” mouselacking the VR1 receptor. Electrophysiological studies of sensoryneurons (dorsal root ganglia) from these animals revealed a markedabsence of responses evoked by noxious stimuli including capsaicin,heat, and reduced pH. These animals did not display any overt signs ofbehavioral impairment and showed no differences in responses to acutenon-noxious thermal and mechanical stimulation relative to wild-typemice. The VR1 (−/−) mice also did not show reduced sensitivity to nerveinjury-induced mechanical or thermal nociception. However, the VR1knock-out mice were insensitive to the noxious effects of intradermalcapsaicin, exposure to intense heat (50-55° C.), and failed to developthermal hyperalgesia following the intradermal administration ofcarrageenan.

The compounds of the present invention are novel VR1 antagonists andhave utility in treating pain, pain associated with inflammatory states,inflammatory thermal hyperalgesia, bladder overactivity, and urinaryincontinence.

SUMMARY OF THE PRESENT INVENTION

The present invention discloses oxazolyl compounds, a method forinhibiting the VR1 receptor in mammals using these compounds, a methodfor controlling pain, pains states associated with inflammatory states,inflammatory thermal hyperalgesia, bladder overactivity, and urinaryincontinence, in mammals, and pharmaceutical compositions includingthose compounds. More particularly, the present invention is directed tocompounds of formula (I)

or a pharmaceutically acceptable salt, amide, ester, prodrug, or salt ofa prodrug thereof, wherein

A is O or —N(R₃); D is —N(R₄), O or S;

R₃ and R₄ are each independently selected from the group consisting ofhydrogen, alkyl, —C(O)alkyl, and —S(O)₂(alkyl);R₁ and R₂ are each independently selected from the group consisting ofhydrogen, alkyl, alkenyl, cyano, nitro, halogen, —OR₅, —OC(O)R₅, —SR₅,—S(O)₂R₅, —S(O)₂OR₅, —S(O)₂N(R₅)(R₆), —N(R₅)(R₆), —N(R₆)C(O)R₅,—N(R₆)C(O)N(R₅)(R₆), —N(R₆)S(O)₂N(R₅)(R₆), —C(O)R₅, —C(O)OR₅,—C(O)N(R₅)(R₆), haloalkyl, -alkylenyl-OR₅, -alkylenyl-OC(O)R₅,-alkylenyl-SR₅, -alkylenyl-S(O)₂R₅, -alkylenyl-S(O)₂OR₅,-alkylenyl-S(O)₂N(R₅)(R₆), -alkylenyl-N(R₅)(R₆), -alkylenyl-N(R₆)C(O)R₅,-alkylenyl-N(R₆)C(O)N(R₅)(R₆), -alkylenyl-N(R₆)S(O)₂N(R₅)(R₆),-alkylenyl-C(O)R₅, -alkylenyl-C(O)OR₅, -alkylenyl-C(O)N(R₅)(R₆), —R₇,and -alkylenyl-R₇; provided that when one of R₁ andR₂ is hydrogen, the other is not hydrogen;R₅ at each occurrence is independently selected from the groupconsisting of hydrogen, alkyl, alkenyl, haloalkyl and benzyl;R₆ at each occurrence is independently selected from the groupconsisting of hydrogen and alkyl;R₇ at each occurrence is independently selected from the groupconsisting of cycloalkyl, cycloalkenyl, heterocycle, aryl andheteroaryl; wherein each R₇ is independently substituted with 0, 1, 2,3, 4 or 5 substituents independently selected from the group consistingof alkyl, alkenyl, halogen, cyano, nitro, hydroxy, alkoxy, haloalkoxy,—S(alkyl), —S(O)₂(alkyl), —N(H)₂, —N(H)(alkyl), —N(alkyl)₂,—N(H)C(O)alkyl, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂, —C(O)N(H)alkyl,—C(O)N(alkyl)₂, —R₈, cyanoalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,haloalkoxyalkyl, -alkylenyl-S(alkyl), -alkylenyl-S(O)₂(alkyl),-alkylenyl-N(H)₂, -alkylenyl-N(H)(alkyl), -alkylenyl-N(alkyl)₂,-alkylenyl-N(H)C(O)alkyl, -alkylenyl-C(O)OH, -alkylenyl-C(O)Oalkyl,-alkylenyl-C(O)NH₂, -alkylenyl-C(O)N(H)alkyl, -alkylenyl-C(O)N(alkyl)₂,and -alkylenyl-R₈;R₈ at each occurrence is independently selected from the groupconsisting of cycloalkyl, cycloalkenyl, heterocycle, aryl andheteroaryl; wherein each R₈ is independently substituted with 0, 1, 2,3, 4 or 5 substituents independently selected from the group consistingof alkyl, alkenyl, halogen, cyano, nitro, hydroxy, alkoxy, haloalkoxy,—S(alkyl), —S(O)₂(alkyl), —N(H)₂, —N(H)(alkyl), —N(alkyl)₂,—N(H)C(O)alkyl, —C(O)OH, —C(O)Oalkyl, —C(O)NH₂, —C(O)N(H)alkyl,—C(O)N(alkyl)₂, cyanoalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,haloalkoxyalkyl, -alkylenyl-S(alkyl), -alkylenyl-S(O)₂(alkyl),-alkylenyl-N(H)₂, -alkylenyl-N(H)(alkyl), -alkylenyl-N(alkyl)₂,-alkylenyl-N(H)C(O)alkyl, -alkylenyl-C(O)OH, -alkylenyl-C(O)Oalkyl,-alkylenyl-C(O)NH₂, -alkylenyl-C(O)N(H)alkyl, and-alkylenyl-C(O)N(alkyl)₂;W and Y are each independently selected from the group consisting of—C(R_(x))(R_(y))— and —N(R_(z))—; provided that when one of W and Y is—N(R_(z))—, then the other is —C(R_(x))(R_(y))—;X is selected from the group consisting of —C(O)—, —C(R_(x))(R_(y))—,—N(R_(z)), —C(R_(x))(R_(y))—C(R_(x))(R_(y))—, —C(O)—C(R_(x))(R_(y))—,—C(R_(x))(R_(y))—C(O)—, —C(R_(x))(R_(y))—N(R_(z))— and—N(R_(z))—C(R_(x))(R_(y))—; provide that when one of W and Y is—N(R_(z))—, then X is selected from the group consisting of—C(R_(x))(R_(y))— and —C(R_(x))(R_(y))—C(R_(x))(R_(y))—;R_(x) and R_(y) at each occurrence are each independently selected fromthe group consisting of hydrogen, alkyl, haloalkyl, —OR_(a),—OC(O)R_(a), —SR_(a), —S(O)₂R_(a), —S(O)₂N(R_(a))(R_(b)), —S(O)₂OR_(a),—N(R_(a))(R_(b)), —N(R_(b))C(O)R_(a), —N(R_(b))C(O)N(R_(a))(R_(b)),—N(R_(b))S(O)₂N(R_(a))(R_(b)), —C(O)OR_(a), —C(O)R_(a),—C(O)N(R_(a))(R_(b)), -alkylenyl-OR_(a), -alkylenyl-OC(O)R_(a),-alkylenyl-SR_(a), -alkylenyl-S(O)₂R_(a),-alkylenyl-S(O)₂N(R_(a))(R_(b)), -alkylenyl-S(O)₂OR_(a),-alkylenyl-N(R_(a))(R_(b)), -alkylenyl-N(R_(b))C(O)R_(a),-alkylenyl-N(R_(b))C(O)N(R_(a))(R_(b)),-alkylenyl-N(R_(b))S(O)₂N(R_(a))(R_(b)), -alkylenyl-C(O)OR_(a),-alkylenyl-C(O)R_(a), -alkylenyl-C(O)N(R_(a))(R_(b)), —R₈ and-alkylenyl-R₈;R_(a) at each occurrence is independently selected from the groupconsisting of hydrogen, alkyl, haloalkyl, —R₈ and -alkylenyl-R₈;R_(b) at each occurrence is independently selected from the groupconsisting of hydrogen, alkyl and haloalkyl;alternatively, R_(a) and R_(b) together with the nitrogen atom to whichthey are attached form a heterocycle ring substituted with 0, 1, 2, 3, 4or 5 substituents independently selected from the group consisting ofhalogen, alkyl and haloalkyl;R_(z), at each occurrence is independently selected from the groupconsisting of hydrogen, alkyl, —C(O)alkyl, and —S(O)₂(alkyl);R₉ at each occurrence is independently selected from the groupconsisting of halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl andhaloalkoxyalkyl; andn is 0, 1, 2, or 3.

DETAILED DESCRIPTION OF THE INVENTION Definition of Terms

As used throughout this specification and the appended claims, thefollowing terms have the following meanings:

The term “alkenyl” as used herein, means a straight or branched chainhydrocarbon containing from 2 to 10 carbon atoms and at least onecarbon-carbon double bond. Examples of alkenyl include, but not limitedto, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl,5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.

The term “alkyl” as used herein, means a straight or branched chainhydrocarbon containing from 1 to 10 carbon atoms. Representativeexamples of alkyl include, but are not limited to, methyl, ethyl,n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl,n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl,2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, andn-decyl.

The term “alkylenyl” or “alkylene” as used herein, means a divalentgroup derived from a straight or branched chain hydrocarbon of from 1 to10 carbon atoms. Representative examples of alkylene or alkylenylinclude, but are not limited to, —CH₂—, —CH(CH₃)—, —C(CH₃)₂—, —CH₂CH₂—,—CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, and —CH₂CH(CH₃)CH₂—.

The term “alkoxy” as used herein, means an alkyl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.Representative examples of alkoxy include, but are not limited to,methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, andhexyloxy.

The term “alkoxyalkyl” as used herein, means an alkoxy group, as definedherein, appended to the parent molecular moiety through an alkyl group,as defined herein. Representative examples of alkoxyalkyl include, butnot limited to, methoxymethyl, methoxyethyl, and ethoxyethyl.

The term “aryl” as used herein, means a phenyl group, or a bicyclic or atricyclic hydrocarbon fused ring system containing zero heteroatomwherein one or more of the fused rings is a phenyl group. Bicyclichydrocarbon fused ring systems are exemplified by a phenyl group fusedto a monocyclic cycloalkyl group, as defined herein, a monocycliccycloalkenyl group, as defined herein, or another phenyl group.Tricyclic hydrocarbon fused ring systems are exemplified by the bicyclicfused hydrocarbon ring system as defined hereinabove, fused to amonocyclic cycloalkyl group, as defined herein, a monocycliccycloalkenyl group, as defined herein, or another phenyl group. The arylgroups of the present invention are appended to the parent moietythrough any substitutable atoms in the group. The aryl groups of thepresent invention can be unsubstituted or substituted. Representativeexamples of aryl include, but are not limited to, phenyl, anthracenyl,naphthyl, fluorenyl, 2,3-dihydro-1H-inden-1-yl,2,3-dihydro-1H-inden-4-yl, inden-1-yl, inden-4-yl, naphthyl, phenyl,5,6,7,8-tetrahydronaphthalen-1-yl, 1,2,3,4-tetrahydronaphthalen-2-yl andtetrahydronaphthyl.

The term “arylalkyl” as used herein, refers to an aryl group, as usedherein, appended to the parent moiety through an alkyl group as definedherein.

The term “cyano” as used herein, refers to —CN.

The term “cyanoalkyl” as used herein, refers to an alkyl group asdefined herein, in which one or two hydrogen atoms are replaced bycyano. Representative examples of cyanoalkyl include, but are notlimited to, 1-methyl-1-cyanoethyl and cyanoethyl.

The term “cycloalkyl” or “cycloalkane” as used herein, refers to amonocyclic, bicyclic or tricyclic saturated hydrocarbon ring systemhaving zero heteroatom. The monocyclic ring system has three to eightcarbon atoms and zero heteroatom. Examples of monocyclic ring systemsinclude cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,and cyclooctyl. The monocyclic cycloalkyl of the present invention maycontain one or two bridges. The term “bridge” refers to a connectionbetween two of the non-adjacent carbon atoms connected by an alkylenebridge between one and three additional carbon atoms. Representativeexamples of monocyclic cycloalkyl that contain such bridge or bridgesinclude, but are not limited to, bicyclo[2.2.1]heptan-1-yl,bicyclo[2.2.1]heptan-2-yl, bicyclo[2.2.1]heptan-1-yl,bicyclo[3.1.1]heptan-6-yl, bicyclo[2.2.2]octan-1-yl and adamantyl. Theterm “cycloalkyl” of the present invention also include a bicycliccycloalkyl or tricyclic cycloalkyl. The bicyclic cycloalkyl of thepresent invention refers to a monocyclic cycloalkyl ring fused toanother monocyclic cycloalkyl group, as defined herein. Representativeexamples of the bicyclic cycloalkyl include, but are not limited to,4a(2H)decahydronaphthalenyl. The bicyclic cycloalkyl groups of thepresent invention may have two of the non-adjacent carbon atomsconnected by an alkylene bridge between one and three additional carbonatoms. Representative examples of the bicyclic cycloalkyl groups thatcontain such connection between two non-adjacent carbon atoms include,but not limited to, octahydro-2,5-methanopentalenyl. The tricycliccycloalkyl group of the present invention refers to a bicycliccycloalkyl ring, as defined hereinabove, fused to another monocycliccycloalkyl group, as defined herein. Representative example of thetricyclic cycloalkyl group includes, but is not limited to,dodecahydro-1H-fluoren-9-yl. The monocyclic, bicyclic and tricycliccycloalkyl groups of the present invention can be unsubstituted orsubstituted, and are connected to the parent molecula moiety through anysubstitutable carbon atom of the group.

The term “cycloalkenyl” or “cycloalkene” as used herein, refers to anon-aromatic, partially unsaturated, monocyclic or bicyclic hydrocarbonring system having zero heteroatom. The monocyclic ring systems have 4,5, 6, 7 or 8 carbon atoms and at least one carbon-carbon double bond.The 4-membered ring systems have one double bond, the 5- or 6-memberedring systems have one or two double bonds, and the 7- or 8-membered ringsystems have one, two or three double bonds. Representative examples ofcycloalkenyl groups include, but not limited to, cyclobutenyl,cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. The term“cycloalkenyl” of the present invention also include a bicyclic fusedring system wherein the monocyclic cycloalkenyl ring is fused to amonocyclic cycloalkyl group, as defined herein, or another monocycliccycloalkenyl group, as defined herein. Representative examples of thebicyclic cycloalkenyl groups include, but not limited to,4,5,6,7-tetrahydro-3aH-indene, octahydronaphthalenyl and1,6-dihydro-pentalene. The cycloalkenyl groups of the present inventioncan be unsubstituted or substituted, and are attached to the parentmolecular moiety through any substitutable carbon atom of the group.

The term “halo” or “halogen” as used herein, means —Cl, —Br, —I or —F.

The term “haloalkoxy” as used herein, refers to an alkoxy group, asdefined herein, in which one, two, three, four, five or six hydrogenatoms are replaced by halogen. Representative examples of haloalkoxyinclude, but are not limited to, chloromethoxy, 2-fluoroethoxy,trifluoromethoxy, hexafluoroethoxy, 2-chloro-3-fluoropentyloxy, andpentafluoroethoxy.

The term “haloalkoxyalkyl” as used herein, refers to a haloalkoxy group,as defined herein, appended to the parent molecular moiety through analkyl group, as defined herein. Examples of haloalkoxyalkyl include, butnot limited to, trifluoromethoxymethyl.

The term “haloalkyl” as used herein, refers to an alkyl group, asdefined herein, in which one, two, three or four, five or six hydrogenatoms are replaced by halogen. Representative examples of haloalkylinclude, but are not limited to, chloromethyl, 2-fluoroethyl,trifluoromethyl, pentafluoroethyl, and 2-chloro-3-fluoropentyl.

The term “heterocycle” or “heterocyclic” as used herein, refers to amonocyclic or bicyclic, non-aromatic, saturated or partially unsaturatedring system. Monocyclic ring systems are exemplified by a 4-memberedring containing one heteroatom independently selected from oxygen,nitrogen and sulfur; or a 5-, 6-, 7-, or 8-membered ring containing one,two or three heteroatoms wherein the heteroatoms are independentlyselected from nitrogen, oxygen and sulfur. The 5-membered ring has 0 or1 double bond. The 6-memebered ring has 0, 1 or 2 double bonds. The 7-or 8-membered ring has 0, 1, 2 or 3 double bonds. Representativeexamples of monocyclic ring systems include, but are not limited to,azetidinyl, azepanyl, azepinyl, diazepinyl, dioxolanyl, dioxanyl,dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl,isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl,oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl,piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl,pyrrolidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydropyridyl,tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl,thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl(thiomorpholine sulfone), thiopyranyl, 1,4-diazepanyl and trithianyl.Bicyclic ring systems are exemplified by any of the above monocyclicring systems fused to a phenyl group, a monocyclic cycloalkenyl group,as defined herein, a monocyclic cycloalkyl group, as defined herein, oran additional monocyclic heterocycle group, as defined herein.Representative examples of bicyclic ring systems include but are notlimited to, benzodioxinyl, benzodioxolyl, benzopyranyl,benzothiopyranyl, 2,3-dihydroindolyl, indolizinyl,tetrahydroisoquinolinyl, tetrahydroquinolinyl,3-azabicyclo[3.2.0]heptyl, 3,6-diazabicyclo[3.2.0]heptyl,octahydrocyclopenta[c]pyrrolyl, hexahydro-1H-furo[3,4-c]pyrrolyl, andoctahydropyrrolo[3,4-c]pyrrolyl. The monocyclic or bicyclic ring systemsas defined herein may have two of the non-adjacent carbon atomsconnected by a heteroatom selected from nitrogen, oxygen or sulfur, orby an alkylene bridge of between one and three additional carbon atoms.Representative examples of monocyclic or bicyclic ring systems thatcontain such connection between two non-adjacent carbon atoms include,but not limited to, 2-azabicyclo[2.2.2]octyl,2-oxa-5-azabicyclo[2.2.2]octyl, 2,5-diazabicyclo[2.2.2]octyl,2-azabicyclo[2.2.1]heptyl, 2-oxa-5-azabicyclo[2.2.1]heptyl,2,5-diazabicyclo[2.2.1]heptyl, 2-azabicyclo[2.1.1]hexyl,5-azabicyclo[2.1.1]hexyl, 3-azabicyclo[3.1.1]heptyl,6-oxa-3-azabicyclo[3.1.1]heptyl, 8-azabicyclo[3.2.1]octyl,8-azabicyclo[3.2.1]oct-8-yl, 3-oxa-8-azabicyclo[3.2.1]octyl,1,4-diazabicyclo[3.2.2]nonyl, 3,10-diazabicyclo[4.3.1]decyl, or8-oxa-3-azabicyclo[3.2.1]octyl, octahydro-1H-4,7-methanoisoindolyl, andoctahydro-1H-4,7-epoxyisoindolyl. The heterocycle groups of theinvention are substituted or unsubstituted, and are connected to theparent molecular moiety through any substitutable carbon or nitrogenatom in the groups. The nitrogen heteroatom may or may not bequaternized, and the nitrogen or sulfur heteroatom may or may not beoxidized. In addition, the nitrogen containing heterocyclic rings may ormay not be N-protected.

The term “heteroaryl” as used herein, refers to monocyclic or bicyclicaromatic ring systems where at least one atom is selected from the groupconsisting of N, O, and S, and the remaining atoms are carbon. Themonocyclic heteroaryl groups have five or six-membered rings containingat least one heteroatom selected from N, O or S and the remainings arecarbon. The five membered rings have two double bonds, and the sixmembered rings have three double bonds. The term “heteroaryl” alsoincludes bicyclic heteroaryl groups where the monocyclic heteroarylring, as defined herein, is fused to a phenyl group, a monocycliccycloalkyl group, as defined herein, a monocyclic cycloalkenyl group, asdefined herein, a monocyclic heterocycle group, as defined herein, or anadditional monocyclic heteroaryl group. Representative examples of themonocyclic and bicyclic heteroaryl groups include, but not limited to,benzothienyl, benzoxazolyl, benzimidazolyl, benzoxadiazolyl,6,7-dihydro-1,3-benzothiazolyl, furyl, imidazolyl,imidazo[1,2-a]pyridinyl, indazolyl, indolyl, isoindolyl, isoxazolyl,isoquinolinyl, isothiazolyl, naphthyridinyl, oxadiazolyl, oxazolyl,pyridoimidazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl,pyrazolyl, pyrrolyl, quinolinyl, thiazolyl, thienyl, triazolyl,thiadiazolyl, tetrazolyl, 1,2,3,4-tetrahydro-1,8-naphthyridin-2-yl, and5,6,7,8-tetrahydroquinolin-5-yl. The heteroaryl groups of the presentinvention can be substituted or unsubstituted, and are connected to theparent molecular moiety through any substitutable carbon or nitrogenatom in the groups. In addition, the nitrogen heteroatom may or may notbe quaternized, the nitrogen and the sulfur atoms in the group may ormay not be oxidized. Also, the nitrogen containing rings may or may notbe N-protected.

The term “heteroatom” as used herein, refers to nitrogen, oxygen orsulfur atom.

The term “hydroxy” or “hydroxyl” as used herein, means an —OH group.

The term “hydroxyalkyl” as used herein, refers to an alkyl group, asdefined herein, in which one or two hydrogen atoms are replaced by ahydroxyl group, as defined herein. Representative examples ofhydroxyalkyl include, but are not limited to, hydroxymethyl,2-hydroxyethyl, 3-hydroxypropyl, 2,3-dihydroxypentyl, and2-ethyl-4-hydroxyheptyl.

The term “nitro” as used herein, means —NO₂.

Compounds of the Present Invention

Compounds of the invention can have the formula (I) as described above.More particularly, compounds of formula (I) can include, but are notlimited to compounds wherein D is —N(R₄) and A is O. Compounds of theinvention can include those wherein D is —N(R₄) and A is —N(R₃) Othercompounds of the invention include those in which A is O and D is S.()Other compounds included in the present invention may be those in whichD is S and A is —N(R₃). Preferred compounds are those in which D is Sand A is —N(R₃), R₁ is hydrogen; R₂ is —R₇, R₃ is hydrogen; R₇ isphenyl; W is —C(R_(x))(R_(y)); Y is —C(R_(x))(R_(y)); X is—C(R_(x))(R_(y)—C(R_(x))(R_(y))—; R_(x) is —O(R_(a)), and R_(y) ishydrogen. Other compounds of the present invention comprise those inwhich both D and A are O. Compounds of the invention can include thosewherein D is O, A is —N(R₃), wherein R₃ is hydrogen Preferred compoundsare those in which D is O, A is —N(R₃), R₃ is hydrogen, R₁ is hydrogenand R₂ is aryl,) more preferably those in which R₂ is phenyl. Thesepreferred compounds include those in which W is —C(R_(x))(R_(y)), Y is—C(R_(x))(R_(y)), and X is —C(O)—C(R_(x))(R_(y))—, wherein R_(x) andR_(y) are hydrogen Other compounds comprised are those in which R₂ isphenyl, W is —C(R_(x))(R_(y)), Y is —C(R_(x))(R_(y)), and X is—C(R_(x))(R_(y))—C(R_(x))(R_(y))—; preferably those in which R_(x) is—OH and R_(y) is hydrogen. Also, preferred compounds include those inwhich R_(x) is —N(R_(a))(R_(b)), and R_(a) and R_(b) are hydrogen, andthose in which R_(x) is —N(R_(a))(R_(b)), R_(a) is —S(O)₂(alkyl), andR_(b) is hydrogen.

Other compounds of the present invention include those in which D is O,A is —N(R₃), wherein R₃ is hydrogen, R₁ is hydrogen, and R₂ iscycloalkyl. Preferably those in which W is —C(R_(x))(R_(y)), Y is—C(R_(x))(R_(y)), and X is —C(O)—C(R_(x))(R_(y))—, wherein R_(x) andR_(y) are hydrogen. Other compounds include those in which D is O, A is—N(R₃), wherein R₃ is hydrogen, R₁ is hydrogen, R₂ is cycloalkyl, W is—C(R_(x))(R_(y)), Y is —C(R_(x))(R_(y)), and X is—C(R_(x))(R_(y))—C(R_(x))(R_(y))—, preferably those in which R_(x) is—OH and R_(y) is hydrogen. Other compounds of the present inventioninclude those in which D is O, A is —N(R₃), wherein R₃ is hydrogen, R₁is hydrogen, and R₂ is alkyl, preferably those in which W is—C(R_(x))(R_(y)), Y is —C(R_(x))(R_(y)), and X is—C(O)—C(R_(x))(R_(y))—, wherein R_(x) and R_(y) are hydrogen Otherpreferred compounds include those in which D is O, A is —N(R₃), whereinR₃ is hydrogen, R₁ is hydrogen, R₂ is alkyl, W is —C(R_(x))(R_(y)), Y is—C(R_(x))(R_(y)), and X is —C(R_(x))(R_(y))—C(R_(x))(R_(y))—, preferablythose in which R_(x) is —OH and R_(y) is hydrogen. The present inventionalso includes compounds in which D is O, A is —N(R₃), wherein R₃ ishydrogen, R₁ is hydrogen, R₂ is alkyl-R₇. Preferred compounds are thosein which R₇ is phenyl, W is —C(R_(x))(R_(y)), Y is —C(R_(x))(R_(y)), andX is —C(O)—C(R_(x))(R_(y))—, wherein R_(x) and R_(y) are hydrogen. Othercompounds included in the present invention are those in which D is O, Ais —N(R₃), wherein R₃ is hydrogen, R₁ is hydrogen, R₂ is alkyl-R₇, R₇ isphenyl, W is —C(R_(x))(R_(y)), Y is —C(R_(x))(R_(y)), and X is—C(R_(x))(R_(y))—C(R_(x))(R_(y))—, preferably those in which R_(x) is—OH and R_(y) is hydrogen. The present invention also includes compoundswherein D is O, A is −1\1(R₃), R₃ is alkyl, W is —C(R_(x))(R_(y)), Y is—C(R_(x))(R_(y)), and X is —C(O)—C(R_(x))(R_(y))—, wherein R_(x) andR_(y) are hydrogen. Other included compounds are those in which D is O,A is —N(R₃), R₃ is —C(O)alkyl, W is —C(R_(x))(R_(y)), Y is—C(R_(x))(R_(y)), and X is —C(O)—C(R_(x))(R_(y))—, wherein R_(x) andR_(y) are hydrogen, and those in which D is O, A is —N(R₃), R₃ is—C(O)alkyl, W is —C(R_(x))(R_(y)), Y is —C(R_(x))(R_(y)), and X is—C(R_(x))(R_(y))—C(R_(x))(R_(y))—, preferably those in which R_(x) is—OH and R_(y) is hydrogen. The present invention also includespharmaceutical compositions comprising therapeutically effective amountsof a compound with a formula (I) as described above, or apharmaceutically acceptable salt, amide, ester or prodrug thereof.

Preparation of Compounds of the Present Invention

The compounds of this invention can be prepared by a variety ofsynthetic procedures. Representative procedures are shown in, but arenot limited to, Schemes 1-5.

Compounds of formula (3) wherein W, X, Y, R₁, R₂, R₉ and n are asdefined in formula (I) can be prepared as shown in Scheme 1 Amines offormula (1), either purchased or prepared using methodologies known toone skilled in the art, can be converted to isothiocyanates of formula(2) by reacting with reagents such as, but not limited to,O,O-dipyridin-2-yl-thiocarbonate, thiophosgene, thiourea/HCl orCS₂/aqueous NH₃. Reaction of the isothiocyanates of formula (2) withazides of formula (5), followed by spontaneous ring closure providesoxazoles of formula (3). The reaction is generally performed in thepresence of triphenylphosphine or tributylphosphine in a solvent suchas, but not limited to, dichloromethane or dioxane, at a temperaturefrom about room temperature to about 100° C.

Azides of formula (5) can be purchased or prepared from compounds offormula (4) wherein X_(b) is I, Cl, Br, mesylate or tosylate by reactingwith sodium azide or trimethylsilylazide in a solvent such as, but notlimited to, acetone, N,N-dimethylformamide, ethanol, dimethylsulfoxide,or hexamethylphosphoramide, at a temperature from about room temperatureto about 100° C.

Imidazoles of formula (9) wherein R₁, R₂, R₉, n, W, X, Y and R₄ are asdefined in formula (I) can be prepared as shown in Scheme 2 Amines offormula (1) can be converted to guanidines of formula (8) using areagent such as, but not limited to, nitrosoguanidine/HCl, cyanamide/HClor reagent of formula (6) wherein R₁₀₁ is tert-butoxycarbonyl orbenzyloxycarbonyl. In the case of where reagents of formula (6) is used,deprotection of the guanidine using methodologies known to one skilledin organic synthesis, transforms compounds of formula (7) wherein R₁₀₂is tert-butoxycarbonyl or benzyloxycarbonyl to compounds of formula (7)wherein R₁₀₂ is hydrogen. Reaction of guanidines of formula (7) whereinR₁₀₂ is hydrogen with compounds of formula (8) wherein X_(a) is aleaving group such as, but not limited to, Cl, Br, I, triflate ormethanesulfonate, (prepared from the corresponding alcohols usingsynthetic routes known to one skilled in the art) followed byspontaneous ring closure, provides imidazoles of formula (9) wherein R₄is hydrogen.

Imidazoles of formula (9) wherein R₄ is hydrogen can be converted tocompounds of formula (9) wherein R₄ is alkyl by reaction with alkylhalides of formula R₄X wherein X is Br, Cl or I in the presence of abase such as, but not limited to, sodium hydride.

Imidazoles of formula (9) wherein R₄ is hydrogen can be converted tocompounds of formula (9) wherein R₄ is —C(O)alkyl by reaction with acylhalides of formula alkylC(O)X wherein X is Cl, Br or I, or anhydrides offormula (R₄CO)₂O wherein R₄ is alkyl, in the presence of a base such astriethylamine.

Imidazoles of formula (9) wherein R₄ is hydrogen can be converted tocompounds of formula (9) wherein R₄ is —S(O)₂alkyl by reaction withcompounds of formula alkylS(O)₂X wherein X is Cl, Br or I in thepresence of a base such as triethylamine.

Thiazoles of formula (11) wherein W, X, Y, R₁, R₂, R₉ and n are asdefined in formula (I), can be prepared from isothiocyanates of formula(2) as depicted in Scheme 3. Reaction of isothiocyanates of formula (2)with gaseous ammonia in a solvent such as, but not limited to, dioxaneor tetrahydrofuran, at about room temperature provides thioureas offormula (10). Conversion of thioureas of formula (10) to thiazoles offormula (11) can be effected using similar reaction conditions employedfor the transformation of compounds of formula (7) to imidazoles offormula (9).

Compounds of formula (15) wherein D, R₁, R₂, R₈, R₉ and n are as definedin formula (I), and G is selected from the group consisting ofcylclopentane, cyclohexane, piperidine and pyrrolidine, and each ring Gis independently unsubstituted or substituted with substituents asdescribed in —W—X—Y— of formula (I), can be prepared as shown in Scheme4.

Alcohols of formula (12) wherein R₁₀₄ is —OH and R₁₀₃ is NO₂ or—N(H)(R₁₀₅) wherein R₁₀₅ is a nitrogen protecting group, can beconverted to compounds of formula (13) by reacting with compounds offormula R₈X_(c) wherein R_(c) is triflate, Br or I, in the presence of ametal catalyst, a ligand, and a base. The reaction is generallyconducted in a solvent such as, but not limited to, dioxane, toluene,N,N-dimethylformamide (DMF), N,N-dimethylacetamide,N-methylpyrrolidinone (NMP) or pyridine. Examples of metal catalystsinclude, but not limited to, palladium diacetate andtris(dibenzylideneacetone)dipalladium(0). Examples of ligands include,but not limited to, 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl andtri-tertbutylphosphine. Examples of bases include, but not limited to,sodium tert-butoxide, sodium hydride, and cesium carbonate.

Alternatively, compounds of formula (13) wherein R₁₀₃ is NO₂ or—N(H)(R₁₀₅) and R₁₀₅ is a nitrogen protecting group can be made from thereaction of formula (12) wherein R₁₀₄ is triflate, Br or I, and R₁₀₃ isNO₂ or —N(H)(R₁₀₅) wherein R₁₀₅ is a nitrogen protecting group, withalcohols of formula R₈OH using the reaction conditions as described inthe preceding paragraph.

Conversion of certain alcohols of formula (12) wherein R₁₀₄ is —OH andR₁₀₃ is NO₂ or —N(H)(R₁₀₅) wherein R₁₀₅ is a nitrogen protecting group,to compounds of formula (13) can also be achieved by reaction withalcohols of formula R₈OH in the presence of diethylazodicarboxylate ordi-(tert-butyl)azodicarboxylate and triphenyl phosphine, a conditionknown as Mitsunobo reaction.

Subsequently, compounds of formula (13) wherein R₁₀₃ is N(H)(R₁₀₅) andR₁₀₅ is a nitrogen protecting group can be converted to compounds offormula (14) by reaction with a suitable deprotecting reagent known toone skilled in the art. Compounds of formula (13) wherein R₁₀₃ is NO₂can be reduced to compounds of formula (14) using a reducing agent.Examples of reducing agents include, but not limited to, lithiumaluminium hydride or tin (or zinc or iron)/HCl. The transformation canalso be effected by hydrogen in the presence of a catalyst, such as, butnot limited to, palladium on carbon or palladium hydroxide on carbon.

Compounds of formula (14) can be converted to compounds of formula (15)using the reaction conditions as described in schemes 1, 2, and 3.

Alternatively, compounds of formula (15) wherein D, R₁, R₂, R₈, R₉ and nare as defined in formula (I), G is selected from the group consistingof cylclopentane, cyclohexane, piperidine and pyrrolidine and each G isindependently unsubstituted or substituted with substituents asdescribed in —W—X—Y— of formula (I), can be prepared from compounds offormula (16) wherein R₁₀₄ is halogen, triflate or —OH (either purchasedor prepared using transformations as described in schemes 1, 2 and 3)using reaction conditions for the transformation of compounds of formula(12) to compounds of formula (13) as described in Scheme 4.

Compounds of formula (19) wherein A, W, X, Y, D, R₁, R₂, R₉ and n are asdefined in formula (I), can be prepared as shown in Scheme 6.

Compounds of formula (17) wherein R₁₀₆ is triflate, Br or I, can bereacted with compounds of formula (18) wherein R₁₀₇ is NH₂ or OH, in thepresence of a ligand, a metal catalyst and a base as shown in Scheme 4,to provide compounds of formula (19) wherein A is O or NH.

Alternatively, compounds of formula (17) wherein R₁₀₆ is NH₂ or OH, canbe reacted with compounds of formula (18) wherein R₁₀₇ is triflate, Bror I, in the presence of a ligand, a metal catalyst and a base as shownin Scheme 4, to provide compounds of formula (19) wherein A is O or NH.

Compounds of formula (19) wherein A is O and W, X, Y, D, R₁, R₂, R₉ andn are as defined in formula (I), can also be obtained by reactingcompounds of formula (17) wherein R₁₀₆ is OH with compounds of formula(18) wherein R₁₀₇ is OH using Mitsunobo conditions.

Compounds of formula (19) wherein A is NH can be converted to compoundsof formula (19) wherein A is N(R₃) wherein R₃ is alkyl, —C(O)alkyl or—S(O)₂(alkyl) can be achieved by reaction with compounds of formula R₃Xwherein X is Cl, Br or I and R₃ is alkyl, —C(O)alkyl or —S(O)₂(alkyl) asdescribed in Scheme 2.

Compounds of formula (19) wherein W, X and Y together with the carbonatoms form a ring selected from the group consisting of cyclohexane andpiperidine and that each ring is independently unsubstituted orsubstituted with substituents as described in W—X—Y of formula (I) canbe either purchased or prepared by known synthetic routes. One exampleof such synthesis involves reduction of compounds of formula (19)wherein W, X and Y together with the carbon atoms form an unsubstitutedor substituted ring selected from the group consisting of benzene andpyridine, using hydrogen gas, in the presence of Raney/nickel and sodiumhydroxide.

Compounds of formula (23) wherein D, R₁, R₂, R₈, R₉ and n are as definedin formula (I), and G is selected from the group consisting ofcylclopentane, cyclohexane, piperidine and pyrrolidine, and each ring Gis independently unsubstituted or substituted with substituents asdescribed in —W—X—Y— of formula (I), can be prepared as shown in scheme7.

Conversion of certain alcohols of formula (12), wherein R₁₀₄ is —OH andR₁₀₃ is NO₂ or —N(H)(R₁₀₅) wherein R₁₀₅ is a nitrogen protecting group,to compounds of formula (20), wherein R₁₀₈ is a “protected” form ofamine such as azido or phthlimido, can be achieved by activation of thehydroxyl group through conversion to, for example, a tosylate ormesylate group followed by reaction with a nitrogen source such assodium azide or sodium phthalimide as in the Gabriel synthesis.Compounds of formula (20) can be converted to compounds of formula (21),wherein R₁₀₉ is hydrogen or a nitrogen protecting group, through areduction and protection sequence known to one skilled in the art.Examples of reducing agents include, but not limited to, lithiumaluminum hydride, hydrazine, and hydrogen in the presence of a catalyst.

Compounds of formula (22) can be converted to compounds of formula (23)using the reaction conditions as described in schemes 1, 2, and 3.

It is understood that the schemes described herein are for illustrativepurposes and that routine experimentation, including appropriatemanipulation of the sequence of the synthetic route, protection of anychemical functionality that are not compatible with the reactionconditions and the removal of such protecting groups are included in thescope of the invention.

Compositions of the Invention

The invention also provides pharmaceutical compositions comprising atherapeutically effective amount of a compound of formula (I) incombination with a pharmaceutically acceptable carrier. The compositionscomprise compounds of the invention formulated together with one or morenon-toxic pharmaceutically acceptable carriers. The pharmaceuticalcompositions can be formulated for oral administration in solid orliquid form, for parenteral injection or for rectal administration.

The term “pharmaceutically acceptable carrier,” as used herein, means anon-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type. Someexamples of materials which can serve as pharmaceutically acceptablecarriers are sugars such as lactose, glucose and sucrose; starches suchas corn starch and potato starch; cellulose and its derivatives such assodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; cocoa butter and suppositorywaxes; oils such as peanut oil, cottonseed oil, safflower oil, sesameoil, olive oil, corn oil and soybean oil; glycols; such a propyleneglycol; esters such as ethyl oleate and ethyl laurate; agar; bufferingagents such as magnesium hydroxide and aluminum hydroxide; alginic acid;pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol,and phosphate buffer solutions, as well as other non-toxic compatiblelubricants such as sodium lauryl sulfate and magnesium stearate, as wellas coloring agents, releasing agents, coating agents, sweetening,flavoring and perfuming agents, preservatives and antioxidants can alsobe present in the composition, according to the judgment of one skilledin the art of formulations.

The pharmaceutical compositions of this invention can be administered tohumans and other mammals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments or drops), bucally or as an oral or nasal spray. Theterm “parenterally,” as used herein, refers to modes of administration,including intravenous, intramuscular, intraperitoneal, intrasternal,subcutaneous, intraarticular injection and infusion.

Pharmaceutical compositions for parenteral injection comprisepharmaceutically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents, solventsor vehicles include water, ethanol, polyols (propylene glycol,polyethylene glycol, glycerol, and the like, and suitable mixturesthereof), vegetable oils (such as olive oil) and injectable organicesters such as ethyl oleate, or suitable mixtures thereof. Suitablefluidity of the composition may be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersions, and by the use of surfactants.

These compositions can also contain adjuvants such as preservativeagents, wetting agents, emulsifying agents, and dispersing agents.Prevention of the action of microorganisms can be ensured by variousantibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, sorbic acid, and the like. It also can bedesirable to include isotonic agents, for example, sugars, sodiumchloride and the like. Prolonged absorption of the injectablepharmaceutical form can be brought about by the use of agents delayingabsorption, for example, aluminum monostearate and gelatin.

In some cases, in order to prolong the effect of a drug, it is oftendesirable to slow the absorption of the drug from subcutaneous orintramuscular injection. This can be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the drug can depend upon its rateof dissolution, which, in turn, may depend upon crystal size andcrystalline form. Alternatively, a parenterally administered drug formcan be administered by dissolving or suspending the drug in an oilvehicle.

Suspensions, in addition to the active compounds, can contain suspendingagents, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar, tragacanth, and mixtures thereof.

If desired, and for more effective distribution, the compounds of theinvention can be incorporated into slow-release or targeted-deliverysystems such as polymer matrices, liposomes, and microspheres. They maybe sterilized, for example, by filtration through a bacteria-retainingfilter or by incorporation of sterilizing agents in the form of sterilesolid compositions, which may be dissolved in sterile water or someother sterile injectable medium immediately before use.

Injectable depot forms are made by forming microencapsulated matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides) Depot injectable formulations also are prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions can be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation also can be a sterile injectablesolution, suspension or emulsion in a nontoxic, parenterally acceptablediluent or solvent such as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that can be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, one or morecompounds of the invention is mixed with at least one inertpharmaceutically acceptable carrier such as sodium citrate or dicalciumphosphate and/or a) fillers or extenders such as starches, lactose,sucrose, glucose, mannitol, and salicylic acid; b) binders such ascarboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia; c) humectants such as glycerol; d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate; e) solutionretarding agents such as paraffin; f) absorption accelerators such asquaternary ammonium compounds; g) wetting agents such as cetyl alcoholand glycerol monostearate; h) absorbents such as kaolin and bentoniteclay; and i) lubricants such as talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate, andmixtures thereof. In the case of capsules, tablets and pills, the dosageform may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using lactose or milk sugar aswell as high molecular weight polyethylene glycols.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well-known in the pharmaceutical formulatingart. They can optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract in a delayedmanner. Examples of materials useful for delaying release of the activeagent can include polymeric substances and waxes.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating carriers such as cocoa butter,polyethylene glycol or a suppository wax which are solid at ambienttemperature but liquid at body temperature and therefore melt in therectum or vaginal cavity and release the active compound.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, microemulsions, solutions, suspensions, syrups andelixirs. In addition to the active compounds, the liquid dosage formsmay contain inert diluents commonly used in the art such as, forexample, water or other solvents, solubilizing agents and emulsifierssuch as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, dimethylformamide, oils (in particular, cottonseed, groundnut,corn, germ, olive, castor, and sesame oils), glycerol,tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid estersof sorbitan, and mixtures thereof.

Besides inert diluents, the oral compositions can also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring, and perfuming agents.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. A desired compound ofthe invention is admixed under sterile conditions with apharmaceutically acceptable carrier and any needed preservatives orbuffers as may be required. Ophthalmic formulation, eardrops, eyeointments, powders and solutions are also contemplated as being withinthe scope of this invention. The ointments, pastes, creams and gels maycontain, in addition to an active compound of this invention, animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc and zinc oxide, or mixtures thereof.

Powders and sprays can contain, in addition to the compounds of thisinvention, lactose, talc, silicic acid, aluminum hydroxide, calciumsilicates and polyamide powder, or mixtures of these substances. Sprayscan additionally contain customary propellants such aschlorofluorohydrocarbons.

Compounds of the invention also can be administered in the form ofliposomes. As is known in the art, liposomes are generally derived fromphospholipids or other lipid substances. Liposomes are formed by mono-or multi-lamellar hydrated liquid crystals that are dispersed in anaqueous medium. Any non-toxic, physiologically acceptable andmetabolizable lipid capable of forming liposomes may be used. Thepresent compositions in liposome form may contain, in addition to thecompounds of the invention, stabilizers, preservatives, and the like.The preferred lipids are the natural and synthetic phospholipids andphosphatidylcholines (lecithins) used separately or together.

Methods to form liposomes are known in the art. See, for example,Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, NewYork, N.Y., (1976), p 33 et seq.

Dosage forms for topical administration of a compound of this inventioninclude powders, sprays, ointments and inhalants. The active compound ismixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives, buffers or propellants. Ophthalmicformulations, eye ointments, powders and solutions are also contemplatedas being within the scope of this invention. Aqueous liquid compositionsof the invention also are particularly useful.

The compounds of the invention can be used in the form ofpharmaceutically acceptable salts, esters, or amides derived frominorganic or organic acids. The term “pharmaceutically acceptable salts,esters and amides,” as used herein, include salts, zwitterions, estersand amides of compounds of formula (I) which are, within the scope ofsound medical judgment, suitable for use in contact with the tissues ofhumans and lower animals without undue toxicity, irritation, allergicresponse, and the like, are commensurate with a reasonable benefit/riskratio, and are effective for their intended use.

The term “pharmaceutically acceptable salt” refers to those salts whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response, and the like, and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well-known in the art. The salts can be prepared insitu during the final isolation and purification of the compounds of theinvention or separately by reacting a free base function with a suitableorganic acid.

Representative acid addition salts include, but are not limited toacetate, adipate, alginate, citrate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate,digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate,fumarate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethansulfonate (isethionate), lactate, maleate,methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, phosphate, glutamate,bicarbonate, p-toluenesulfonate and undecanoate.

Also, the basic nitrogen-containing groups can be quaternized with suchagents as lower alkyl halides such as methyl, ethyl, propyl, and butylchlorides, bromides and iodides; dialkyl sulfates such as dimethyl,diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl,lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkylhalides such as benzyl and phenethyl bromides and others. Water oroil-soluble or dispersible products are thereby obtained.

Examples of acids which can be employed to form pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acidand such organic acids as oxalic acid, maleic acid, succinic acid, andcitric acid.

Basic addition salts can be prepared in situ during the final isolationand purification of compounds of this invention by reacting a carboxylicacid-containing moiety with a suitable base such as the hydroxide,carbonate or bicarbonate of a pharmaceutically acceptable metal cationor with ammonia or an organic primary, secondary or tertiary amine.Pharmaceutically acceptable salts include, but are not limited to,cations based on alkali metals or alkaline earth metals such as lithium,sodium, potassium, calcium, magnesium, and aluminum salts, and the like,and nontoxic quaternary ammonia and amine cations including ammonium,tetramethylammonium, tetraethylammonium, methylamine, dimethylamine,trimethylamine, triethylamine, diethylamine, ethylamine and the such as.Other representative organic amines useful for the formation of baseaddition salts include ethylenediamine, ethanolamine, diethanolamine,piperidine, and piperazine.

The term “pharmaceutically acceptable ester,” as used herein, refers toesters of compounds of the invention which hydrolyze in vivo and includethose that break down readily in the human body to leave the parentcompound or a salt thereof. Examples of pharmaceutically acceptable,non-toxic esters of the invention include C₁-to-C₆ alkyl esters andC₅-to-C₇ cycloalkyl esters, although C₁-to-C₄ alkyl esters arepreferred. Esters of the compounds of formula (I) can be preparedaccording to conventional methods. Pharmaceutically acceptable esterscan be appended onto hydroxy groups by reaction of the compound thatcontains the hydroxy group with acid and an alkylcarboxylic acid such asacetic acid, or with acid and an arylcarboxylic acid such as benzoicacid. In the case of compounds containing carboxylic acid groups, thepharmaceutically acceptable esters are prepared from compoundscontaining the carboxylic acid groups by reaction of the compound withbase such as triethylamine and an alkyl halide, alkyl trifilate, forexample with methyl iodide, benzyl iodide, cyclopentyl iodide. They alsocan be prepared by reaction of the compound with an acid such ashydrochloric acid and an alkylcarboxylic acid such as acetic acid, orwith acid and an arylcarboxylic acid such as benzoic acid.

The term “pharmaceutically acceptable amide,” as used herein, refers tonon-toxic amides of the invention derived from ammonia, primary C₁-to-C₆alkyl amines and secondary C₁-to-C₆ dialkyl amines. In the case ofsecondary amines, the amine can also be in the form of a 5- or6-membered heterocycle containing one nitrogen atom. Amides derived fromammonia, C₁-to-C₃ alkyl primary amides and C₁-to-C₂ dialkyl secondaryamides are preferred. Amides of the compounds of formula (I) can beprepared according to conventional methods. Pharmaceutically acceptableamides can be prepared from compounds containing primary or secondaryamine groups by reaction of the compound that contains the amino groupwith an alkyl anhydride, aryl anhydride, acyl halide, or aroyl halide.In the case of compounds containing carboxylic acid groups, thepharmaceutically acceptable esters are prepared from compoundscontaining the carboxylic acid groups by reaction of the compound withbase such as triethylamine, a dehydrating agent such as dicyclohexylcarbodiimide or carbonyl diimidazole, and an alkyl amine, dialkylamine,for example with methylamine, diethylamine, piperidine. They also can beprepared by reaction of the compound with an acid such as sulfuric acidand an alkylcarboxylic acid such as acetic acid, or with acid and anarylcarboxylic acid such as benzoic acid under dehydrating conditions aswith molecular sieves added. The composition can contain a compound ofthe invention in the form of a pharmaceutically acceptable prodrug.

The term “pharmaceutically acceptable prodrug” or “prodrug,” as usedherein, represents those prodrugs of the compounds of the inventionwhich are, within the scope of sound medical judgment, suitable for usein contact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response, and the like, commensurate witha reasonable benefit/risk ratio, and effective for their intended use.Prodrugs of the invention can be rapidly transformed in vivo to a parentcompound of formula (I), for example, by hydrolysis in blood. A thoroughdiscussion is provided in T. Higuchi and V. Stella, Pro-drugs as NovelDelivery Systems, V. 14 of the A.C.S. Symposium Series, and in Edward B.Roche, ed., Bioreversible Carriers in Drug Design, AmericanPharmaceutical Association and Pergamon Press (1987).

The invention contemplates pharmaceutically active compounds eitherchemically synthesized or formed by in vivo biotransformation tocompounds of formula (I).

Methods of the Invention

Compounds and compositions of the invention are useful for amelioratingor preventing disorders involving VR1 receptor activation such as, butnot limited to, inflammatory thermal hyperalgesia, bladder overactivity,and urinary incontinence as described by Nolano, M. et al., Pain, Vol.81, pages 135-145, (1999); Caterina, M. J. and Julius, D., Annu. Rev.Neurosci. Vol. 24, pages 487-517 (2001); Caterina, M. J. et al., ScienceVol. 288 pages 306-313 (2000); Caterina, M. J. et al., Nature Vol. 389pages 816-824 (1997); Fowler, C. Urology Vol. 55 pages 60-64 (2000); andDavis, J. et al., Nature Vol. 405 pages 183-187.

The present invention also provides pharmaceutical compositions thatcomprise compounds of the present invention. The pharmaceuticalcompositions comprise compounds of the present invention that may beformulated together with one or more non-toxic pharmaceuticallyacceptable carriers.

EXAMPLES

The following Examples are intended as an illustration of and not alimitation upon the scope of the invention as defined in the appendedclaims.

Example 18-({5-[4-(trifluoromethyl)phenyl]-1,3-oxazol-2-yl}amino)-3,4-dihydronaphthalen-2(1H)-one Example 1A 2-bromo-1-(4-tert-butylphenyl)ethanone

A solution of 4-tert-butylacetophenone (5 g, 28.4 mmol) in acetic acid(2 mL) was carefully (the reaction was exothermic) treated with Br₂(1.46 mL, 28.5 mmol), followed by 48% aq. HBr (0.015 mL, 0.132 mmol).The reaction was stirred at room temperature for 4 hours, then waspoured onto ice and was extracted with diethyl ether. The organic phasewas concentrated and was then chromatographed on silica gel, elutingwith 5% ethyl acetate-hexane, followed by 10% ethyl acetate-hexane, toafford the title compound as a pale brown oil, 1.305 g (18%). ¹H NMR(DMSO-d₆) δ 7.94 (d, 2H, J=8.5 Hz), 7.58 (d, 2H, J=8.5 Hz), 4.90 (s,2H), 1.31 (s, 9H); MS (ESI⁺) m/z 255 (M+H).

Example 1B 2-azido-1-(4-tert-butylphenyl)ethanone

To a solution of the product of Example 1A (985 mg, 3.86 mmol) in 45 mLacetone was added NaN₃ (0.505 g, 7.07 mmol), and the mixture stirredovernight at room temperature. The reaction mixture was poured intosaturated NaCl solution and extracted with dichloromethane. The extractswere washed with saturated NaCl solution, dried over Na₂SO₄, andconcentrated in vacuo to afford the title compound as a yellow oil (715mg, 85%). ¹H NMR (DMSO-d₆) δ 7.88 (d, 2H, J=8.5 Hz), 7.57 (d, 2H, J=8.5Hz), 4.86 (s, 2H), 1.31 (s, 9H); MS (ESI⁺) m/z 218 (M+H).

Example 1C tert-butyl 7-ethoxy-1-naphthylcarbamate

To 8-amino-2-naphthol (10 g, 62.9 mmol) in 200 mL tetrahydrofuran wasadded di-tert-butyl dicarbonate (13.4 g, 62.8 mmol) in 20 mLtetrahydrofuran, and the reaction mixture was refluxed overnight. Thereaction mixture was cooled to room temperature and concentrated invacuo. The residue was dissolved in ethyl acetate, washed with saturatedNa₂CO₃ solution and water, dried over Na₂SO₄, filtered and concentrated.A solution of the concentrate in N,N-dimethylformamide (60 mL) wastreated with Cs₂CO₃ (32.2 g, 98.8 mmol) and iodoethane (4.4 mL, 8.46 g,53.5 mmol), and the mixture was vigorously stirred at 60° for 3 h. Themixture was then cooled to rt, poured into H₂O, and extracted with ethylacetate. The extracts were washed with H₂O and brine, dried over MgSO₄,filtered, and evaporated in vacuo to afford the title compound as abrown oil (14.47 g, 80%). ¹H NMR (DMSO-d₆) δ 9.14 (s, 1H), 7.81 (d, 1H,8.9 Hz), 7.61 (d, 1H, J=8.2 Hz), 7.54 (d, 1H, 7.8 Hz), 7.37 (d, 1H,J=2.7 Hz), 7.28 (t, 1H, J=7.8 Hz), 7.15 (dd, 1H, J=8.9 Hz, 2.7 Hz), 4.16(q, 2H, J=7.1 Hz), 1.50 (s, 9H), 1.09 (t, 3H, J=7.0 Hz); MS (ESI⁺) m/z310 (M+Na)⁺.

Example 1D 7-ethoxy-1-naphthylamine

To a solution of the product of Example 1C (14.47 g, 50.4 mmol) indioxane (30 mL) at 0° C. was added 4N HCl in dioxane (60 mL, 240 mmol).The reaction mixture was stirred at room temperature for 3.5 hours,diluted with 3 volumes of diethyl ether. The resulting dark brownprecipitate was collected by filtration. It was then treated withsaturated NaHCO₃ solution and was extracted with ethyl acetate. Thesolution was dried over MgSO₄, filtered and evaporated in vacuo to yieldthe title compound (4.88 g, 52%).

Example 1E 7-ethoxy-5,8-dihydronaphthalen-1-amine

The product of Example 1D (1.8 g, 9.63 mmol) and tert-butanol (2.13 g,28.8 mmol) were dissolved in tetrahydrofuran (20 mL) in a 3-neck 1000 mLround-bottom flask, and the solution was cooled to −78° C. Ammonia (˜35mL) was condensed into the flask, then lithium metal was added (wire,225 mg, 32.4 mmol) in portions over 10 min. The reaction mixture wasstirred at −78° C. for 1 h, quenched with methanol (50 mL) and H₂O (50mL). The reaction was allowed to stir overnight at room temperature toallow NH₃ to evaporate, then it was diluted with ethyl acetate (300 mL),washed with H₂O and brine, dried over Na₂SO₄, filtered and concentrated.The residue was purified on silica gel, eluting with 15%-25% ethylacetate-hexanes, to afford the title compound as a brown oil (999 mg,55%). ¹H NMR (DMSO-d₆) δ 6.82 (t, 1H, J=7.6 Hz), 6.44 (d, 1H, J=7.1 Hz),6.35 (d, 1H, J=7.5 Hz), 4.80 (s, 2H), 4.78 (t, 1H, J=3.8 Hz), 3.78 (q,2H, J=7.1 Hz), 3.36 (q, 2H, 4.8 Hz), 3.00 (t, 2H, J=4.9 Hz), 1.26 (t,3H, J=7.1 Hz); MS (DCI⁺) m/z 190 (M+H).

Example 1F 2-ethoxy-8-isothiocyanato-1,4-dihydronaphthalene

A solution of the product of Example 1E (200 mg, 1.06 mmol) indichloromethane (2.5 mL) was added to a solution of O,O-dipyridin-2-ylthiocarbonate (246 mg, 1.06 mmol) in dichloromethane (5 mL) at roomtemperature. After stirring at room temperature for 18 hours, themixture was concentrated, then filtered through silica gel and elutedwith 5% ethyl acetate-hexane. Evaporation of the filtrate in vacuoafforded the title compound as a pale pink solid, 225 mg (92%). ¹H NMR(DMSO-d₆) δ 7.21-7.27 (m, 3H), 4.86 (t, 1H, J=3.6 Hz), 3.81 (q, 2H,J=7.0 Hz), 3.49 (q, 2H, 4.4 Hz), 3.35 (t, 2H, J=5.2 Hz), 1.27 (t, 3H,J=7.0 Hz); MS (DCI⁺) m/z 232 (M+H).

Example 1G 2-azido-1-[4-(trifluoromethyl)phenyl]ethanone

The title compound was prepared using the procedure as described inExample 1B, substituting 2-bromo-1-[4-(trifluoromethyl)phenyl]ethanonefor 2-bromo-1-(4-tert-butylphenyl)ethanone.

Example 1HN-(7-ethoxy-5,8-dihydronaphthalen-1-yl)-5-[4-(trifluoromethyl)phenyl]-1,3-oxazol-2-amine

A solution of the product of Example 1F (398 mg, 1.72 mmol), the productof Example 1G (473 mg, 2.07 mmol), and triphenyl phosphine (542 mg, 2.07mmol) in dioxane (9 mL) was heated at 85° C. for 30 min. The solutionwas cooled to room temperature and evaporated in vacuo. The residue waschromatographed on silica gel, eluting with 25% ethyl acetate-hexane toafford the title compound as a yellow solid (150 mg, 22%). ¹H NMR(DMSO-d₆) δ 9.38 (s, 1H), 7.76 (m, 4H), 7.65 (d, 1H, J=8.5 Hz), 7.62 (s,1H), 7.18 (t, 1H, J=8.2 Hz), 6.97 (d, 1H, J=8.4 Hz), 4.85 (m, 1H), 3.79(q, 2H, J=6.7 Hz), 3.49 (m, 2H), 3.36 (m, 2H), 1.26 (t, 3H, J=6.8 Hz);MS (ESI⁺) m/z 401 (M+H)⁺.

Example 1I8-({5-[4-(trifluoromethyl)phenyl]-1,3-oxazol-2-yl}amino)-3,4-dihydronaphthalen-2(1H)-one

A solution of the product of Example 1H (150 mg, 0.375 mmol) intetrahydrofuran (2.3 mL) was treated with 2N HCl (0.76 mL, 1.52 mmol),and the mixture was heated at 40° C. for 1 hour. After cooling to roomtemperature, the solution was brought to pH 8 with saturated NaHCO₃solution, and extracted with ethyl acetate. The organic extracts werewashed with H₂O, dried over Na₂SO₄, filtered and evaporated in vacuo tothe title compound as a brown residue (140 mg, 100%). ¹H NMR (DMSO-d₆) δ9.56 (s, 1H), 7.78 (m, 4H), 7.67 (d, 1H, J=7.8 Hz), 7.62 (s, 1H), 7.22(t, 1H, J=7.8 Hz), 7.06 (d, 1H, J=7.4 Hz), 3.58 (s, 2H), 3.36 (m, 2H),3.06 (t, 2H, J=6.8 Hz); MS (ESI⁺) m/z 373 (M+H)⁺.

Example 28-({5-[4-(trifluoromethyl)phenyl]-1,3-oxazol-2-yl}amino)-1,2,3,4-tetrahydronaphthalen-2-ol

The product of Example 1I (60 mg, 0.161 mmol) in ethanol (6 mL) wastreated at 0° C. with NaBH₄ (7 mg, 0.184 mmol). The reaction was stirredat 0° C. for 1 hour and was then poured into H₂O and extracted withethyl acetate. The extracts were dried over Na₂SO₄, and concentrated invacuo. The residue was chromatographed on silica gel eluting with70%-85% ethyl acetate-hexane to afford the title compound as a tan solid(34 mg, 56%). ¹H NMR (DMSO-d₆) δ 9.33 (s, 1H), 7.78 (m, 4H), 7.62 (s,1H), 7.55 (d, 1H, J=7.4 Hz), 7.11 (m, 1H), 6.88 (d, 1H, J=7.2 Hz), 4.83(d, 1H, J=4.1 Hz), 3.92 (m, 1H), 2.69-2.98 (m, 4H), 1.86 (m, 1H), 1.62(m, 1H); MS (ESI⁺) m/z 375 (M+H).

Example 38-{[5-(4-tert-butylphenyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-olExample 3A5-(4-tert-butylphenyl)-N-(7-ethoxy-5,8-dihydronaphthalen-1-yl)-1,3-oxazol-2-amine

The title compound was prepared using the procedure as described inExample 1H, substituting the product of Example 1B for the product ofExample 1G.

Example 3B8-{[5-(4-tert-butylphenyl)-1,3-oxazol-2-yl]amino}-3,4-dihydronaphthalen-2(1H)-one

The title compound was prepared using the procedure of Example 1H,substituting the product of Example 3A for the product of Example 1H.

Example 3C8-{[5-(4-tert-butylphenyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-ol

The title compound was prepared using the procedure of Example 2,substituting the product of Example 3B for the product of Example 1I. ¹HNMR (DMSO-d₆) δ 9.07 (s, 1H), 7.58 (d, 1H, J=5.4 Hz), 7.46 (m, 3H), 7.30(s, 1H), 7.08 (t, 1H, J=7.8 Hz), 6.83 (d, 1H, J=7.1 Hz), 4.80 (d, 1H,J=4.0 Hz), 3.91 (m, 1H), 2.72-2.96 (m, 4H), 1.86 (m, 1H), 1.62 (m, 1H),1.29 (s, 9H); MS (ESI⁺) m/z 363 (M+H).

Example 4(2S)-8-{[5-(4-tert-butylphenyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-ol

The title compound was obtained by chromatographing the product ofExample 3 using chiral HPLC (ChiralPak AD column, eluent:hexane-ethanol=75/25, flow rate=15 mL/min). [α]_(D) ²⁰=−48.0° (c 1.0,MeOH).

Example 5(2R)-8-{[5-(4-tert-butylphenyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-ol

The title compound was obtained by chromatographing the product ofExample 3 using chiral HPLC (ChiralPak AD column, eluent:hexane-ethanol=75/25, flow rate=15 mL/min). [α]_(D) ²⁰=+43.2° (c 1.0,MeOH).

Example 68-{[5-(4-chlorophenyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-olExample 6A 2-azido-1-(4-chlorophenyl)ethanone

The title compound was prepared using the procedure as described inExample 1B, substituting 2-bromo-1-[4-chlorophenyl]ethan-1-one for theproduct of Example 1A.

Example 6B5-(4-chlorophenyl)-N-(7-ethoxy-5,8-dihydronaphthalen-1-yl)-1,3-oxazol-2-amine

The title compound was prepared using the procedure as described inExample 1H, substituting the product of Example 6A for the product ofExample 1G.

Example 6C8-{[5-(4-chlorophenyl)-1,3-oxazol-2-yl]amino}-3,4-dihydronaphthalen-2(1H)-one

The title compound was prepared using the procedure as described inExample 1I, substituting the product of Example 6B for the product ofExample 1H.

Example 6D8-{[5-(4-chlorophenyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-ol

The title compound was prepared using the procedure as described inExample 2, substituting the product of Example 6C for the product ofExample 1I. ¹H NMR (DMSO-d₆) δ 9.16 (s, 1H), 7.43-7.57 (m, 6H), 7.09 (t,1H, J=7.4 Hz), 6.83 (d, 1H, J=7.0 Hz), 4.80 (d, 1H, J=3.7 Hz), 3.92 (m,1H), 2.72-2.98 (m, 4H), 1.86 (m, 1H), 1.61 (m, 1H); MS (ESI⁺) m/z341/343 (M+H, ³⁵Cl/³⁷Cl).

Example 78-{[5-(4-pyrrolidin-1-ylphenyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-olExample 7A 2-azido-1-(4-pyrrolidin-1-ylphenyl)ethanone

The title compound was prepared using the procedure as described inExample 1B, substituting 2-bromo-1-(4-pyrrolidin-1-ylphenyl)ethanone forthe product of Example 1A.

Example 7BN-(7-ethoxy-5,8-dihydronaphthalen-1-yl)-5-(4-pyrrolidin-1-ylphenyl)-1,3-oxazol-2-amine5-(4-chlorophenyl)-N-(7-ethoxy-5,8-dihydronaphthalen-1-yl)-1,3-oxazol-2-amine

The title compound was prepared using the procedure as described inExample 1H, substituting the product of Example 7A for the product ofExample 1G.

Example 7C8-{[5-(4-pyrrolidin-1-ylphenyl)-1,3-oxazol-2-yl]amino}-3,4-dihydronaphthalen-2(1H)-one

The title compound was prepared using the procedure as described inExample 1I, substituting the product of Example 7B for the product ofExample 1H.

Example 7D8-{[5-(4-pyrrolidin-1-ylphenyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-ol

The title compound was prepared using the procedure as described inExample 2, substituting the product of Example 7C for the product ofExample 1I. ¹H NMR (DMSO-d₆) δ 8.86 (s, 1H), 7.61 (d, 2H, J=7.2 Hz),7.37 (d, 1H, J=8.9 Hz), 7.07 (t, 1H, J=7.8 Hz), 7.02 (s, 1H), 6.80 (d,1H, J=8.2 Hz), 6.57 (d, 2H, J=8.8 Hz), 4.79 (d, 1H, J=4.1 Hz), 3.91 (m,1H), 3.25 (m, 4H), 2.66-2.97 (m, 4H), 1.99 (m, 4H), 1.89 (m, 1H), 1.62(m, 1H); MS (ESI⁺) m/z 376 (M+H).

Example 88-{[5-(4-bromophenyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-olExample 8A 2-azido-1-(4-bromophenyl)ethanone

The title compound was prepared using the procedure as described inExample 1B, substituting 2-bromo-1-(4-bromophenyl)ethanone for theproduct of Example 1A.

Example 8B5-(4-bromophenyl)-N-(7-ethoxy-5,8-dihydronaphthalen-1-yl)-1,3-oxazol-2-amine

The title compound was prepared using the procedure as described inExample 1H, substituting the product of Example 8A for the product ofExample 1G.

Example 8C8-{[5-(4-bromophenyl)-1,3-oxazol-2-yl]amino}-3,4-dihydronaphthalen-2(1H)-one

The title compound was prepared using the procedure as described inExample 1I, substituting the product of Example 8B for the product ofExample 1H.

Example 8D8-{[5-(4-bromophenyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-ol

The title compound was prepared using the procedure as described inExample 2, substituting the product of Example 8C for the product ofExample 1I. ¹H NMR

(DMSO-d₆) δ9.17 (s, 1H), 7.43-7.57 (m, 6H), 7.10 (t, 1H, J=7.3 Hz), 6.81(d, 1H, J=6.8 Hz), 4.80 (d, 1H, J=3.9 Hz), 3.90 (m, 1H), 2.68-2.96 (m,4H), 1.82 (m, 1H), 1.60 (m, 1H); MS (ESI⁺) m/z 385/387 (M+H, ⁷⁹Br/⁸¹Br).

Example 98-{[5-(4-methylphenyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-olExample 9A 2-azido-1-(4-methylphenyl)ethanone

The title compound was prepared using the procedure as described inExample 1B, substituting 2-bromo-1-(4-methylphenyl)ethanone for theproduct of Example 1A.

Example 9BN-(7-ethoxy-5,8-dihydronaphthalen-1-yl)-5-(4-methylphenyl)-1,3-oxazol-2-amine

The title compound was prepared using the procedure as described inExample 1H, substituting the product of Example 9A for the product ofExample 1G.

Example 9C8-{[5-(4-methylphenyl)-1,3-oxazol-2-yl]amino}-3,4-dihydronaphthalen-2(1H)-one

The title compound was prepared using the procedure as described inExample 1I, substituting the product of Example 9B for the product ofExample 1H.

Example 9D8-{[5-(4-methylphenyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-ol

The title compound was prepared using the procedure as described inExample 2, substituting the product of Example 9C for the product ofExample 1I. ¹H NMR (DMSO-d₆) δ 9.05 (s, 1H), 7.58 (m, 1H), 7.44 (m, 2H),7.29 (s, 1H), 7.19 (m, 2H), 7.06 (t, 1H, J=7.5 Hz), 6.83 (d, 1H, J=7.0Hz), 4.80 (d, 1H, J=4.0 Hz), 3.92 (m, 1H), 2.72-2.96 (m, 4H), 2.31 (s,3H), 1.84 (m, 1H), 1.63 (m, 1H); MS (ESI⁺) m/z 321 (M+H).

Example 108-{[5-(4-methoxyphenyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-olExample 10A 2-azido-1-(4-methoxyphenyl)ethanone

The title compound was prepared using the procedure as described inExample 1B, substituting 2-bromo-1-(4-methoxyphenyl)ethanone for theproduct of Example 1A.

Example 10BN-(7-ethoxy-5,8-dihydronaphthalen-1-yl)-5-(4-methoxyphenyl)-1,3-oxazol-2-amine

The title compound was prepared using the procedure as described inExample 1H, substituting the product of Example 10A for the product ofExample 1G.

Example 10C8-{[5-(4-methoxyphenyl)-1,3-oxazol-2-yl]amino}-3,4-dihydronaphthalen-2(1H)-one

The title compound was prepared using the procedure as described inExample 1I, substituting the product of Example 10B for the product ofExample 1H.

Example 10D8-{[5-(4-methoxyphenyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-ol

The title compound was prepared using the procedure as described inExample 2, substituting the product of Example 10C for the product ofExample 1I. ¹H NMR (DMSO-d₆) δ 8.98 (s, 1H), 7.59 (d, 1H, J=7.8 Hz),7.49 (d, 2H, J=8.8 Hz), 7.20 (s, 1H), 7.08 (t, 1H, J=7.6 Hz), 7.00 (d,2H, J=8.8 Hz), 6.82 (d, 1H, J=7.4 Hz), 4.79 (d, 1H, J=4.1 Hz), 3.93 (m,1H), 3.78 (s, 3H), 2.74-2.98 (m, 4H), 1.85 (m, 1H), 1.63 (m, 1H); MS(ESI⁺) m/z 337 (M+H).

Example 118-[(5-phenyl-1,3-oxazol-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-2-olExample 11A 2-azido-1-phenylethanone

The title compound was prepared using the procedure as described inExample 1B, substituting 2-bromo-1-phenylethanone for the product ofExample 1A.

Example 1I BN-(7-ethoxy-5,8-dihydronaphthalen-1-yl)-5-phenyl-1,3-oxazol-2-amine

The title compound was prepared using the procedure as described inExample 1H, substituting the product of Example 1I A for the product ofExample 1G.

Example 1I C8-[(5-phenyl-1,3-oxazol-2-yl)amino]-3,4-dihydronaphthalen-2(1H)-one

The title compound was prepared using the procedure as described inExample 1I, substituting the product of Example 1I B for the product ofExample 1H.

Example 1I D8-[(5-phenyl-1,3-oxazol-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-2-ol

The title compound was prepared using the procedure as described inExample 2, substituting the product of Example 1I C for the product ofExample 1I. ¹H NMR (DMSO-d₆) 9.11 (s, 1H), 7.59 (m, 3H), 7.41 (t, 2H,J=7.7 Hz), 7.37 (s, 1H), 7.25 (t, 1H, J=7.5 Hz), 7.09 (t, 1H, J=7.5 Hz),6.84 (d, 1H, J=7.1 Hz), 4.80 (d, 1H, J=4.1 Hz), 3.93 (m, 1H), 2.73-2.99(m, 4H), 1.86 (m, 1H), 1.62 (m, 1H); MS (ESI⁺) m/z 307 (M+H).

Example 128-{[5-(1-adamantyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-olExample 12A 1-(1-adamantyl)-2-azidoethanone

The title compound was prepared using the procedure as described inExample 1B, substituting 1-(1-adamantyl)-2-bromoethanone for the productof Example 1A.

Example 12B5-(1-adamantyl)-N-(7-ethoxy-5,8-dihydronaphthalen-1-yl)-1,3-oxazol-2-amine

The title compound was prepared using the procedure as described inExample 1H, substituting the product of Example 12A for the product ofExample 1G.

Example 12C8-{[5-(1-adamantyl)-1,3-oxazol-2-yl]amino}-3,4-dihydronaphthalen-2(1H)-one

The title compound was prepared using the procedure as described inExample 1I, substituting the product of Example 12B for the product ofExample 1H.

Example 12D8-{[5-(1-adamantyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-ol

The title compound was prepared using the procedure as described inExample 2, substituting the product of Example 12C for the product ofExample 1I. ¹H NMR (DMSO-d₆) δ 8.64 (s, 1H), 7.55 (d, 1H, J=7.7 Hz),7.05 (t, 1H, J=7.6 Hz), 6.77 (d, 1H, J=7.1 Hz), 6.41 (s, 1H), 4.76 (d,1H, J=4.1 Hz), 3.90 (m, 1H), 2.72-2.94 (m, 3H), 1.63-2.05 (m, 18H); MS(ESI⁺) m/z 365 (M+H)⁺.

Example 138-[(5-methyl-1,3-oxazol-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-2-olExample 13A 1-azidoacetone

The title compound was prepared using the procedure as described inExample 1B, substituting 1-chloroacetone for the product of Example 1A.

Example 13BN-(7-ethoxy-5,8-dihydronaphthalen-1-yl)-5-methyl-1,3-oxazol-2-amine

The title compound was prepared using the procedure as described inExample 1H, substituting the product of Example 13A for the product ofExample 1G.

Example 13C8-[(5-methyl-1,3-oxazol-2-yl)amino]-3,4-dihydronaphthalen-2(1H)-one

The title compound was prepared using the procedure as described inExample 1I, substituting the product of Example 13B for the product ofExample 1H.

Example 13D8-[(5-methyl-1,3-oxazol-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-2-ol

The title compound was prepared using the procedure as described inExample 2, substituting the product of Example 13C for the product ofExample 1I. ¹H NMR (DMSO-d₆) m/z δ 8.64 (s, 1H), 7.55 (d, 1H, J=8.1 Hz),7.03 (t, 1H, J=7.8 Hz), 6.76 (d, 1H, J=7.4 Hz), 6.48 (s, 1H), 4.77 (d,1H, J=4.1 Hz), 3.90 (m, 1H), 2.63-2.93 (m, 4H), 2.20 (s, 3H), 1.83 (m,1H), 1.60 (m, 1H); MS (ESI⁺) m/z 245 (M+H)⁺.

Example 148-{[5-(2-methylphenyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-olExample 14A 2-azido-1-(2-methylphenyl)ethanone

The title compound was prepared using the procedure as described inExample 1B, substituting 2-bromo-1-(2-methylphenyl)ethanone for theproduct of Example 1A.

Example 14BN-(7-ethoxy-5,8-dihydronaphthalen-1-yl)-5-(2-methylphenyl)-1,3-oxazol-2-amine

The title compound was prepared using the procedure as described inExample 1H, substituting the product of Example 14A for the product ofExample 1G.

Example 14C8-{[5-(2-methylphenyl)-1,3-oxazol-2-yl]amino}-3,4-dihydronaphthalen-2(1H)-one

The title compound was prepared using the procedure as described inExample 1I, substituting the product of Example 14B for the product ofExample 1H.

Example 14D8-{[5-(2-methylphenyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-ol

The title compound was prepared using the procedure as described inExample 2, substituting the product of Example 14C for the product ofExample 1I. ¹H NMR (DMSO-d₆) δ 9.11 (s, 1H), 7.54-7.63 (m, 2H),7.07-7.30 (m, 5H), 6.84 (d, 1H, J=7.1 Hz), 4.81 (d, 1H, J=4.1 Hz), 3.92(m, 1H), 2.68-2.99 (m, 4H), 2.40 (s, 3H), 1.84 (m, 1H), 1.62 (m, 1H); MS(ESI⁺) m/z 321 (M+H)⁺.

Example 158-{[5-(3-methylphenyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-olExample 15A 2-azido-1-(3-methylphenyl)ethanone

The title compound was prepared using the procedure as described inExample 1B, substituting 2-bromo-1-(3-methylphenyl)ethanone for theproduct of Example 1A.

Example 15BN-(7-ethoxy-5,8-dihydronaphthalen-1-yl)-5-(3-methylphenyl)-1,3-oxazol-2-amine

The title compound was prepared using the procedure as described inExample 1H, substituting the product of Example 15A for the product ofExample 1G.

Example 15C8-{[5-(3-methylphenyl)-1,3-oxazol-2-yl]amino}-3,4-dihydronaphthalen-2(1H)-one

The title compound was prepared using the procedure as described inExample 1I, substituting the product of Example 15B for the product ofExample 1H.

Example 15D8-{[5-(3-methylphenyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-ol

The title compound was prepared using the procedure as described inExample 2, substituting the product of Example 15C for the product ofExample 1I. ¹H NMR (DMSO-d₆) δ 9.08 (s, 1H), 7.58 (d, 1H, J=7.3 Hz),7.26-7.39 (m, 4H), 7.04-7.12 (m, 2H), 6.83 (d, 1H, J=7.2 Hz), 4.81 (d,1H, J=4.1 Hz), 3.93 (m, 1H), 2.73-2.97 (m, 4H), 2.33 (s, 3H), 1.86 (m,1H), 1.61 (m, 1H); MS (ESI⁺) m/z 321 (M+H).

Example 168-[(5-benzyl-1,3-oxazol-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-2-olExample 16A 1-bromo-3-phenylacetone

To a suspension of CuBr (0.143 g, 0.997 mmol) in 25 mL dry ether wasslowly added 1M phenylmagnesium bromide (10 mL, 10 mmol). Epibromohydrin(0.87 mL, 10.5 mmol) was then added dropwise. The reaction mixture wasallowed to stir at −78° C. to room temperature overnight, poured intoH₂O and extracted with ether. The extracts were washed with H₂O andbrine, dried over Na₂SO₄, filtered and evaporated in vacuo. The crudealcohol thus obtained was dissolved in acetone (400 mL) and chilled inice, and to this solution was added dropwise 6 mL of Jones reagent(prepared by dissolution of 2.67 g CrO₃ in 2.5 mL H₂SO₄, followed bydilution with H₂O to 10 mL). The reaction mixture was stirred at 0° C.for 15 min and was then evaporated in vacuo. The residue was taken up inethyl acetate, washed repeatedly with water and once with brine, driedover Na₂SO₄, filtered and evaporated to afford the ketone product as abrown oil (1.6 g, 75%).

¹H NMR (DMSO-d₆) δ 7.17-7.35 (m, 5H), 4.45 (s, 2H), 3.94 (s, 2H); MS(DCI⁺) m/z 230 (M+NH₄ ⁺).

Example 16B 1-azido-3-phenylacetone

The title compound was prepared using the procedure as described inExample 1B, substituting the product of Example 16A for the product ofExample 1A.

Example 16C5-benzyl-N-(7-ethoxy-5,8-dihydronaphthalen-1-yl)-1,3-oxazol-2-amine

The title compound was prepared using the procedure as described inExample 1H, substituting the product of Example 16B for the product ofExample 1G.

Example 16D8-[(5-benzyl-1,3-oxazol-2-yl)amino]-3,4-dihydronaphthalen-2(1H)-one

The title compound was prepared using the procedure as described inExample 1I, substituting the product of Example 16C for the product ofExample 1H.

Example 16E8-[(5-benzyl-1,3-oxazol-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-2-ol

The title compound was prepared using the procedure as described inExample 2, substituting the product of Example 16D for the product ofExample 1I. ¹H NMR (DMSO-d₆) δ 8.72 (s, 1H), 7.56-7.63 (m, 3H),7.23-7.37 (m, 3H), 7.02 (t, 1H, J=7.5 Hz), 6.77 (d, 1H, J=7.3 Hz), 6.56(s, 1H), 4.74 (d, 1H, J=3.7 Hz), 3.93 (s, 2H), 3.81 (m, 1H), 2.70-2.90(m, 4H), 1.81 (m, 1H), 1.58 (m, 1H); MS (ESI⁺) m/z 321 (M+H)⁺.

Example 178-[(5-tert-butyl-1,3-oxazol-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-2-olExample 17A 1-azido-3,3-dimethylbutan-2-one

A mixture of 1-bromopinacolone (0.5 mL, 3.7 mmol) and NaN₃ (0.48 g, 7.38mmol) in 50 mL acetone was stirred overnight at room temperature. It wasthen poured into brine and extracted with dichloromethane. The extractswere washed with brine, were dried over Na₂SO₄, filtered, and wereevaporated to afford the title compound as a yellow oil (524 mg, 100%).¹H NMR (DMSO-d₆) δ 4.39 (s, 2H), 1.10 (s, 9H); MS (DCI⁺) m/z 142 (M+H)⁺.

Example 17B5-tert-butyl-N-(7-ethoxy-5,8-dihydronaphthalen-1-yl)-1,3-oxazol-2-amine

The title compound was prepared using the procedure as described inExample 1H, substituting the product of Example 17A for the product ofExample 1G.

Example 17C8-[(5-tert-butyl-1,3-oxazol-2-yl)amino]-3,4-dihydronaphthalen-2(1H)-one

The title compound was prepared using the procedure as described inExample 1I, substituting the product of Example 17B for the product ofExample 1H.

Example 17D8-[(5-tert-butyl-1,3-oxazol-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-2-ol

The title compound was prepared using the procedure as described inExample 2, substituting the product of Example 17C for the product ofExample 1I. ¹H NMR (DMSO-d₆) δ 8.66 (s, 1H), 7.53 (d, J=7.8 Hz, 1H),7.01 (t, J=7.8 Hz, 1H), 6.75 (d, J=7.5 Hz, 1H), 6.44 (s, 1H), 4.76 (d,J=3.7 Hz, 1H), 3.94 (m, 1H), 2.61-2.99 (m, 4H), 1.84 (m, 1H), 1.60 (m,1H), 1.22 (s, 9H); MS (ESI⁺) m/z 287 (M+H)⁺.

Example 188-(methyl{5-[4-(trifluoromethyl)phenyl]-1,3-oxazol-2-yl}amino)-1,2,3,4-tetrahydronaphthalen-2-olExample 18A 8-amino-1,2,3,4-tetrahydronaphthalen-2-ol

To the hydrogenation reaction vessel was charged 5 g of8-amino-2-naphthanol, 0.2 g of 50% w/w NaOH, 100 ml ethanol, and 2 g ofRaney Ni (wet 40 wt % load). The vessel was vacuum purged with hydrogenseveral times before heating to 85° C. and maintaining a hydrogenpressure of 1300 psi. The mixture was filtered after 6 hrs, and thefiltrate concentrated to yield a brown solid. Isolated yield 4.97 g(97%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.44-1.68 (m, 1H), 1.79-1.94 (m,1H), 2.20 (dd, J=16.48, 7.63 Hz, 1H), 2.56-2.85 (m, 3H), 3.85-3.99 (m,1H), 4.63 (s, 2H), 4.75 (d, J=4.12 Hz, 1H), 6.30 (d, J=7.48 Hz, 1H),6.44 (d, J=7.78 Hz, 1H), 6.78 (t, J=7.63 Hz, 1H). ¹³C NMR (126 MHz,DMSO-d₆) δ ppm 27.35, 31.41, 33.36, 65.81, 111.35, 116.48, 119.13,125.53, 136.00, 146.12.

Example 18B7-{[tert-butyl(dimethyl)silyl]oxy}-5,6,7,8-tetrahydronaphthalen-1-amine

A mixture of the product of Example 18A (2.33 g, 14.3 mmol),tert-butylchlorodimethylsilane (2.6 g, 17.2 mmol), and imidazole (2.9 g,42.3 mmol) was stirred in 40 mL of dichloromethane at rt overnight. Themixture was then washed several times with water and once with brine.Drying over Na₂SO₄, filtered and evaporation afforded the product as adark purple oil, 2.6 g (65%). ¹H NMR (DMSO-d₆) δ 6.77 (dd, J=7.8, 7.4Hz, 1H), 6.42 (d, J=7.8 Hz, 1H), 6.28 (d, J=7.4 Hz, 1H), 4.7 (br s, 2H),4.11 (m, 1H), 2.75 (m, 3H), 2.24 (m, 1H), 1.82 (m, 1H), 1.63 (m, 1H),0.88 (s, 9H), 0.09 (s, 6H); MS (ESI⁺) m/z 278 (M+H)⁺.

Example 18Ctert-butyl[(8-isothiocyanato-1,2,3,4-tetrahydronaphthalen-2-yl)oxy]dimethylsilane

A solution of the product of Example 18B, 2-(tert-butyldimethylsilyl)-ol(1.4 g, 5.07 mmol) and di-2-pyridyl thionocarbonate (1.07 g, 4.61 mmol)in 30 mL dichloromethane was stirred at room temperature overnight. Themixture was evaporated, then the residue was taken up in 2 mLdichloromethane and filtered through silica gel, eluting with 5% ethylacetate-hexane. Evaporation of the filtrate afforded the product as adark red oil (1.165 g, 72%). ¹H NMR (DMSO-d₆) δ 7.21 (m, 3H), 4.27 (m,1H), 2.58-3.09 (m, 4H), 1.90 (m, 1H), 1.77 (m, 1H), 0.90 (s, 9H), 0.14(s, 6H).

Example 18DN-(7-{[tert-butyl(dimethyl)silyl]oxy}-5,6,7,8-tetrahydronaphthalen-1-yl)-5-[4-(trifluoromethyl)phenyl]-1,3-oxazol-2-amine

The title compound was prepared using the procedure as described inExample 1H, substituting the product of Example 18C for the product ofExample 1F.

Example 18EN-(7-{[tert-butyl(dimethyl)silyl]oxy}-5,6,7,8-tetrahydronaphthalen-1-yl)-N-methyl-5-[4-(trifluoromethyl)phenyl]-1,3-oxazol-2-amine

The product of Example 18D (300 mg, 0.615 mmol) in 5 mLN,N-dimethylformamide was treated with NaH (60% dispersion, 32 mg, 0.8mmol) at rt. After stirring for 5 minutes, iodomethane (0.15 mL, 2.4mmol) was added. The reaction was stirred at rt for 24 h, then it waspoured into ethyl acetate and washed several times with water and oncewith brine. The organic layer was dried over Na₂SO₄ and wasconcentrated. The concentrate was purified on silica gel, eluting with5% ethyl acetate-hexane and afforded the title compound as a brown oil(56 mg, 18%).

Example 18F8-(methyl{5-[4-(trifluoromethyl)phenyl]-1,3-oxazol-2-yl}amino)-1,2,3,4-tetrahydronaphthalen-2-ol

A solution of the product of Example 18E (56 mg, 0.112 mmol) in 6 mL oftetrahydrofuran was treated with a solution of tetrabutylammoniumfluoride (1M-in-tetrahydrofuran, 1 mL, 1 mmol). The reaction mixture wasstirred at rt for 4 h, then the solvent was evaporated, and the residuewas chromatographed on silica gel, eluting with 70% ethylacetate-hexane, to afford the title compound as a tan foam (27 mg, 62%).¹H NMR (DMSO-d₆) δ 7.70 (d, J=8.4 Hz, 2H), 7.58 (d, J=8.3 Hz, 2H), 7.57(s, 1H), 7.11-7.22 (m, 3H), 4.78 (d, J=3.7 Hz, 1H), 3.86 (m, 1H), 3.38(s, 3H), 2.73-2.98 (m, 3H), 2.37 (m, 1H), 1.89 (m, 1H), 1.63 (m, 1H); MS(ESI⁺) m/z 389 (M+H)⁺.

Example 19N-[5-(4-tert-butylphenyl)-1,3-oxazol-2-yl]-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide

The product of Example 3C (76 mg, 0.21 mmol) in 2 mL tetrahydrofuran wasstirred with acetic anhydride (0.026 mL, 0.275 mmol) and triethylamine(0.088 mL, 0.63 mmol) at rt for 3 h. The reaction mixture was thendiluted with ethyl acetate and washed with water and brine. The organicphase was dried over Na₂SO₄, filtered and concentrated. The residue waschromatographed on silica gel, eluting with 35% ethyl acetate-hexane andthen 60% ethyl acetate-hexane to afford the title compound as a tan foam(38 mg, 45%). ¹H NMR (DMSO-d₆) δ 8.03 (s, 1H), 7.48 (m, 4H), 7.10 (m,2H), 6.82 (m, 1H), 4.72 (d, J=3.8 Hz, 1H), 3.92 (m, 1H), 2.84-3.02 (m,3H), 2.73 (s, 3H), 2.44 (m, 1H), 1.86 (m, 1H), 1.61 (m, 1H), 1.27 (s,9H); MS (ESI⁺) m/z 405 (M+H)⁺.

Example 20N¹-(5-p-methylphenyloxazol-2-yl)-5,6,7,8-tetrahydronaphthalene-1,7-diamineExample 20A (7-Hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)carbamic acidbenzyl ester

Benzylchloroformate (6.96 g, 40.8 mmol) was added dropwise to a solutionof Example 18B (10.3 g, 37.1 mmol,) and diisopropylethylamine (7.20 g,55.7 mmol) in 120 mL CH₂Cl₂ at 0° C. The mixture was stirred for 18hours gradually warming to ambient temperature after which the volatileswere evaporated under reduced pressure. The residue was purified onsilica gel eluting with 25% EtOAc/hexanes which yielded the benzylcarbamate as a light brown oil (15.2 g, 36.9 mmol). This product wastaken up in 100 mL THF followed by addition of 1.79 g (111 mmol) oftriethylamine trihydrofluoride. After 24 hours, the mixture wasconcentrated under reduced pressure and the residue partitioned betweenEtOAc and 1N aq. HCl. The separated organic layer was washed with 1N aq.HCl, brine, dried (Na₂SO₄), and concentrated under reduced pressure. Thecrude product was triturated with Et₂O, and the solid was collected byvacuum filtration and dried under vacuum at 50° C. resulting 8.82 g(80%) of the title compound as a white solid. ¹H NMR (DMSO-d₆) δ 8.82(s, 1H), 7.45-7.30 (m, 5H), 7.14 (d, J=7.0 Hz, 1H), 7.05 (t, J=7.0 Hz,1H), 6.90 (d, J=7.0 Hz, 1H), 5.12 (s, 2H), 4.77 (d, J=3.7 Hz, 1H), 3.87(m, 1H), 2.86 (m, 2H), 2.72 (m, 1H), 2.43 (m, 1H), 1.84 (m, 1H), 1.58(m, 1H); MS (ESI⁺) m/z 298 (M+H)⁺.

Example 20B (7-Azido-5,6,7,8-tetrahydronaphthalen-1-yl)carbamic acidbenzyl ester

To a suspension of the product of Example 20A (5.05 g, 17.0 mmol) in 100mL CH₂Cl₂ containing diisopropylethylamine (3.29 g, 25.5 mmol) at 0° C.was added methanesulfonyl chloride (2.15 g, 18.9 mmol) dropwise. Afterstirring 2 hours, the volatiles were evaporated under reduced pressure.The residue was partitioned between EtOAc and water, and the separatedorganic layer was washed with 1N aq. HCl, saturated NaHCO₃, brine, dried(Na₂SO₄), filtered and concentrated under reduced pressure. The crudeproduct was dissolved in 60 mL DMF followed by addition of sodium azide.The mixture was heated to 75° C. for 1.5 hour then concentrated underreduced pressure. The residue was taken up in EtOAc and washed withwater, brine, dried (Na₂SO₄), filtered and concentrated under reducedpressure. The crude product was triturated with 1:1 Et₂O:hexane and thesolid collected by vacuum filtration and dried in air. The result was4.68 g (85%) of the title compound as a pale orange solid. ¹H NMR(DMSO-d₆) δ 8.95 (s, 1H), 7.45-7.30 (m, 5H), 7.19 (d, J=7 Hz, 1H), 7.10(t, J=7 Hz, 1H), 6.94 (d, J=7 Hz, 1H), 5.13 (s, 2H), 4.00 (m, 1H), 2.96(m, 1H), 2.83 (m, 2H), 2.62 (m, 1H), 1.99 (m, 1H), 1.74 (m, 1H); MS(ESI⁺) m/z 323 (M+H)⁺.

Example 20C (7-Amino-5,6,7,8-tetrahydronaphthalen-1-yl)carbamic acidbenzyl ester

Polymer supported triphenylphosphine (9.5 g, 28 mmol) was added to theproduct of Example 20B (4.6 g, 14 mmol) in THF (100 mL) containing 1.3 g(71 mmol) H₂O. The mixture was stirred for 48 hours at ambienttemperature, then diluted with THF and filtered through a pad of celite.The filter cake was washed with 3 solvents systems sequentiallycomprising 100% CH₃OH, 1:1 CH₃OH:CH₂Cl₂, and 100% CH₂Cl₂. The filtratewas concentrated under reduced pressure to provide 3.5 g (83%) of thetitle compound. ¹H NMR (DMSO-d₆) δ 8.81 (s, 1H), 7.45-7.30 (m, 5H), 7.13(d, J=8 Hz, 1H), 7.05 (t, J=7 Hz, 1H), 6.90 (d, J=7 Hz, 1H), 5.12 (s,2H), 3.00-2.65 (m, 4H), 2.23 (m, 1H), 1.84 (m, 1H), 1.59 (br s, 2H),1.37 (m, 1H); MS (ESI⁺) m/z 297 (M+H)⁺.

Example 20D(8-Benzyloxycarbonylamino-1,2,3,4-tetrahydronaphthalen-2-yl)carbamicacid tert-butyl ester

Di-t-butyldicarbonate (2.59 g, 11.9 mmol) was added to a solution of theproduct of Example 20C (3.52 g, 11.9 mmol) and diisopropylethylamine(2.30 g, 17.8 mmol) in 50 mL CH₂Cl₂ at ambient temperature. The mixturewas stirred 18 hours and the volatiles were evaporated under reducedpressure. The residue was taken up in EtOAc and washed with 1N aq. HCl,saturated NaHCO₃, brine, dried (Na₂SO₄), filtered and concentrated underreduced pressure. Flash chromatography (30% EtOAc/hexanes) yielded 3.73g (79%) of the title compound as a white solid. ¹H NMR (DMSO-d₆) δ 8.87(br s, 1H), 7.45-7.30 (m, 5H), 7.10 (m, 2H), 6.93 (m, 2H), 5.12 (s, 2H),3.80 (m, 1H), 2.90 (m, 1H), 2.81 (m, 2H), 2.38 (m, 1H), 1.87 (m, 1H),1.55 (m, 1H), 1.40 (s, 9H); MS (ESI⁺) m/z 419 (M+Na)⁺.

Example 20E (8-Amino-1,2,3,4-tetrahydronaphthalen-2-yl)carbamic acidtert-butyl ester

To a solution of the product of Example 20D (3.73 g, 9.41 mmol) in 80 mLmethanol was added 0.75 g 20% Pd(OH)₂/C. The mixture was shaken under 60psi H₂ for 4 hours. The catalyst was then filtered and the filtrateconcentrated under reduced pressure. The crude product was purified byflash chromatography eluting with 2% to 5% CH₃OH/CH₂Cl₂ which gave 2.33g (94%) of the title compound as a white solid. ¹H NMR (DMSO-d₆) δ 6.91(br d, 1H), 6.77 (t, J=7.6 Hz, 1H), 6.42 (d, J=7.1 Hz, 1H), 6.29 (d,J=7.1 Hz, 1H), 4.69 (br s, 2H), 3.63 (m, 1H), 2.68 (m, 3H), 2.12 (m,1H), 1.83 (m, 1H), 1.52 (m, 1H), 1.40 (s, 9H); MS (ESI⁺) m/z 263 (M+H)⁺.

Example 20F (8-Isothiocyanato-1,2,3,4-tetrahydronaphthalen-2-yl)carbamicacid tert-butyl ester

The title compound was prepared using the procedure as described inExample 1F, substituting the product of Example 20E (1.02 g, 3.89 mmol)for 7-ethoxy-5,8-dihydronaphthalen-1-amine. ¹H NMR (DMSO-d₆) δ 7.25-7.10(m, 3H), 7.00 (m, 1H), 3.70 (m, 1H), 2.98 (m, 1H), 2.81 (m, 2H), 2.57(m, 1H), 1.90 (m, 1H), 1.58 (m, 1H), 1.41 (s, 9H); MS (ESI⁺) m/z 305(M+H)⁺.

Example 20G[8-(5-p-methylphenyloxazol-2-ylamino)-1,2,3,4-tetrahydronaphthalen-2-yl]carbamicacid tert-butyl ester

The title compound was prepared using the procedure as described inExample 1H, substituting the product of Example 20F (188 mg, 0.618 mmol)for the product of Example 1F and the product of Example 9A (130 mg,0.741 mmol) for the product of Example 1G. The crude product waspurified by flash chromatography eluting with 2% to 5% CH₃OH/CH₂Cl₂followed by 60% EtOAc/hexanes which gave 215 mg (83%) of the titlecompound as a yellow amorphous solid. ¹H NMR (DMSO-d₆) δ 9.06 (br s,1H), 7.60 (d, J=7.8 Hz, 1H), 7.45 (d, J=8.1 Hz, 2H), 7.29 (s, 1H), 7.23(d, J=8.1 Hz, 2H), 7.10 (t, J=7.8 Hz, 1H), 6.98 (br d, 1H), 6.84 (d,J=7.5 Hz, 1H), 3.65 (m, 1H), 3.02 (m, 1H), 2.83 (m, 2H), 2.42 (m, 1H),2.31 (s, 3H), 1.87 (m, 1H), 1.58 (m, 1H), 1.39 (s, 9H); MS (ESI⁺) m/z420 (M+H)⁺.

Example 20HN¹-(5-p-methylphenyloxazol-2-yl)-5,6,7,8-tetrahydronaphthalene-1,7-diamine

Hydrogen chloride in dioxane (4N, 7 mL, 28 mmol) was added to asuspension of 199 mg (0.474 mmol) of the product of Example 20G in 1 mLdioxane. After stirring 45 minutes, the mixture was quenched with 3NNaOH solution, then diluted with EtOAc and poured into water. Theseparated organic phase was washed with brine, dried (Na₂SO₄), filteredand concentrated under reduced pressure. The crude product wastriturated with Et₂O and the solid was collected by vacuum filtration.The result was 92 mg (61%) of the title compound as a pale pink solid.¹H NMR (DMSO-d₆) δ 9.02 (br s, 1H), 7.57 (d, J=7.1 Hz, 1H), 7.45 (d,J=8.1 Hz, 2H), 7.28 (s, 1H), 7.23 (d, J=8.1 Hz, 2H), 7.08 (t, J=7.8 Hz,1H), 6.83 (d, J=7.1 Hz, 1H), 3.05-2.70 (m, 4H), 2.31 (m, 4H), 1.85 (m,3H), 1.42 (m, 1H); MS (ESI⁺) m/z 320 (M+H)⁺.

Example 21N¹-[5-(4-Trifluoromethylphenyl)oxazol-2-yl]-5,6,7,8-tetrahydronaphthalene-1,7-diamineExample 21A{8-[5-(4-Trifluoromethylphenyl)oxazol-2-ylamino]-1,2,3,4-tetrahydro-naphthalen-2-yl}carbamicacid tert-butyl ester

The title compound was prepared using the procedure as described inExample 1H, substituting the product of Example 20F (215 mg, 0.706 mmol)for the product of Example 1F, and the product of Example 1G (194 mg,0.848 mmol). The crude product was purified by flash chromatographyeluting with 20% EtOAc/hexane which gave 123 mg (37%) of the titlecompound as a white solid. ¹H NMR (DMSO-d₆) δ 9.32 (br s, 1H), 7.75 (m,4H), 7.60 (s, 1H), 7.55 (d, J=7.8 Hz, 1H), 7.12 (t, J=7.8 Hz, 1H), 6.98(br d, 1H), 6.88 (d, J=7.5 Hz, 1H), 3.64 (m, 1H), 3.02 (m, 1H), 2.84 (m,2H), 2.42 (m, 1H), 1.87 (m, 1H), 1.60 (m, 1H), 1.39 (s, 9H); MS (ESI⁺)m/z 474 (M+H)⁺.

Example 21BN¹-[5-(4-Trifluoromethylphenyl)oxazol-2-yl]-5,6,7,8-tetrahydronaphthalene-1,7-diamine

The title compound was prepared using the procedure as described inExample 20H substituting the product of Example 21A (120 mg, 0.253 mmol)for the product of Example 20G. The crude product was purified bytrituration with Et₂O/hexanes which resulted in 36 mg (38%) of the titlecompound as a white solid. ¹H NMR (DMSO-d₆) δ 9.32 (br s, 1H), 7.75 (m,4H), 7.60 (s, 1H), 7.55 (d, J=7.8 Hz, 1H), 7.10 (t, J=7.8 Hz, 1H), 6.87(d, J=7.8 Hz, 1H), 3.05-2.70 (m, 4H), 2.30 (m, 1H), 1.82 (m, 3H), 1.43(m, 1H); MS (ESI⁺) m/z 374 (M+H)⁺.

Example 22N¹-[5-(2-Fluoro-4-trifluoromethylphenyl)oxazol-2-yl]-5,6,7,8-tetrahydro-naphthalene-1,7-diamineExample 22A 2-Azido-1-(2-fluoro-4-trifluoromethylphenyl)ethanone

The title compound was prepared using the procedure as described inExample 1B, substituting2-Bromo-1-(2-fluoro-4-trifluoromethylphenyl)ethanone for2-bromo-1-(4-tert-butylphenyl)ethanone.

Example 22B{8-[5-(2-Fluoro-4-trifluoromethylphenyl)oxazol-2-ylamino]-1,2,3,4-tetrahydro-naphthalen-2-yl}carbamicacid tert-butyl ester

The title compound was prepared using the procedure as described inExample 1H, substituting the product of Example 20F (415 mg, 1.36 mmol)for the product of Example 1F and the product of Example 22A (404 mg,1.63 mmol) for the product of Example 1G. The crude product was purifiedby flash chromatography eluting with 20% to 60% EtOAc/hexanes which gave107 mg (16%) of the title compound as a yellow solid.

Example 22CN¹-[5-(2-Fluoro-4-trifluoromethylphenyl)oxazol-2-yl]-5,6,7,8-tetrahydro-naphthalene-1,7-diamine

Iodotrimethylsilane (52 mg, 0.260 mmol) was added dropwise to a solutionof the product of Example 22B (107 mg, 0.218 mmol) in 1 mL CH₂Cl₂ atambient temperature. After 15 minutes the reaction was diluted withCH₂Cl₂ and quenched with 1N aq NaOH solution. The mixture was stirred 15minutes and then poured into water. The separated organic layer waswashed with brine, dried (Na₂SO₄), filtered and concentrated in vacuo.The crude product was triturated with Et₂O/hexanes and the solidcollected by vacuum filtration and dried under high vacuum. The resultwas 36 mg (42%) of the title compound as a white solid. ¹H NMR (DMSO-d₆)δ 9.42 (br s, 1H), 7.75 (m, 3H), 7.52 (d, J=8.1 Hz, 1H), 7.44 (d, J=3.7Hz, 1H), 7.11 (t, J=7.5 Hz, 1H), 6.88 (d, J=7.5 Hz, 1H), 3.05-2.70 (m,4H), 2.30 (m, 1H), 1.86 (m, 1H), 1.70 (br s, 2H), 1.43 (m, 1H); MS(ESI⁺) m/z 392 (M+H)⁺.

Example 23N-[8-(5-p-methylphenyloxazol-2-ylamino)-1,2,3,4-tetrahydronaphthalen-2-yl]methanesulfonamideExample 23A(7-Methanesulfonylamino-5,6,7,8-tetrahydronaphthalen-1-yl)carbamic acidbenzyl ester

Methanesulfonyl chloride (176 mg, 1.54 mmol) was added dropwise to asolution of the product from Example 20C (381 mg, 1.29 mmol) anddiisopropylethylamine (332 mg, 2.57 mmol) in 15 mL CH₂Cl₂ at ambienttemperature. The mixture was stirred 30 minutes, diluted with methylenechloride and poured into water. The separated organic phase was washedwith 1N aq HCl, brine, dried (Na₂SO₄), filtered and concentrated underreduced pressure. Flash chromatography (4% CH₃OH/CH₂Cl₂) yielded 281 mg(58%) of the title compound as a white amorphous solid. ¹H NMR (DMSO-d₆)δ 8.92 (s, 1H), 7.45-7.30 (m, 5H), 7.22 (d, J=7.1 Hz, 1H), 7.15 (m, 1H),7.08 (t, J=7.5 Hz, 1H), 6.93 (m, 1H), 5.13 (s, 2H), 3.51 (m, 1H), 3.02(m, 1H), 2.96 (s, 3H), 2.85 (m, 2H), 2.50 (m, 1H+DMSO), 2.01 (m, 1H),1.61 (m, 1H); MS (ESI⁺) m/z 375 (M+H)⁺.

Example 23BN-(8-Amino-1,2,3,4-tetrahydronaphthalen-2-yl)methanesulfonamide

The title compound was prepared using the procedure as described inExample 20E substituting the product of Example 23A (280 mg, 0.748 mmol)for the product Example 20D. Flash chromatography (5% to 10%CH₃OH/CH₂Cl₂) gave 129 mg (72%) of the title compound as a white solid.¹H NMR (DMSO-d₆) δ 7.20 (d, J=7.5 Hz, 1H), 6.79 (t, J=7.8 Hz, 1H), 6.43(m, 1H), 6.30 (m, 1H), 4.74 (s, 2H), 3.55 (m, 1H), 2.99 (s, 3H), 2.75(m, 3H), 2.22 (m, 1H), 1.95 (m, 1H), 1.58 (m, 1H); MS (DCI⁺) m/z 241(M+H)⁺.

Example 23CN-(8-Isothiocyanato-1,2,3,4-tetrahydronaphthalen-2-yl)methanesulfonamide

The title compound was prepared using the procedure as described inExample 1F, substituting the product of Example 23B (125 mg, 0.529 mmol)for 7-ethoxy-5,8-dihydronaphthalen-1-amine. Flash chromatography elutingwith 3% to 6% CH₃OH/CH₂Cl₂ gave 131 mg (89%) of the title compound as awhite solid. ¹H NMR (DMSO-d₆) δ 7.24 (m, 2H), 7.19 (d, J=7.8 Hz, 1H),7.14 (m, 1H), 3.66 (m, 1H), 3.09 (m, 1H), 3.00 (s, 3H), 2.85 (m, 2H),2.66 (m, 1H), 2.01 (m, 1H), 1.69 (m, 1H); MS (DCI⁺) m/z 300 (m+NH₄)⁺.

Example 23DN-[8-(5-p-methylphenyloxazol-2-ylamino)-1,2,3,4-tetrahydronaphthalen-2-yl]methanesulfonamide

The title compound was prepared using the procedure as described inExample 1H, substituting the product of Example 23C (128 mg, 0.453 mmol)for the product of Example 1F and the product of Example 9A (95 mg,0.544 mmol) for the product of Example 1G. The crude product waspurified by flash chromatography eluting with 2% to 5% CH₃OH/CH₂Cl₂followed by 100% EtOAc which gave 116 mg (64%) of the title compound asa tan solid. ¹H NMR (DMSO-d₆) δ 9.13 (s, 1H), 7.61 (d, J=7.5 Hz, 1H),7.46 (d, J=8.1 Hz, 2H), 7.30 (s, 1H), 7.23 (m, 3H), 7.11 (t, J=7.8 Hz,1H), 6.85 (d, J=7.5 Hz, 1H), 3.58 (m, 1H), 3.11 (m, 1H), 2.99 (s, 3H),2.87 (m, 2H), 2.56 (m, 1H), 2.31 (s, 3H), 2.01 (m, 1H), 1.66 (m, 1H); MS(ESI⁺) m/z 398 (M+H)⁺.

Example 248-(5-Phenylthiazol-2-ylamino)-1,2,3,4-tetrahydronaphthalen-2-ol Example24A[7-(tert-Butyldimethylsilyloxy)-5,6,7,8-tetrahydronaphthalen-1-yl]thiourea

A solution of the product of Example 18C (1.25 g, 3.91 mmol) in THF (50mL) was treated with 7N methanolic NH₃ (5.6 mL, 39.1 mmol), and themixture was stirred at room temperature for 6 hours. The mixture waspartitioned between EtOAc and H₂O, and the separated organic phase waswashed with brine, dried over Na₂SO₄, filtered and evaporated underreduced pressure. Silica gel chromatography (98:2 to 95:5 CH₂Cl₂:CH₃OHeluant) provided the title compound as a pale yellow solid, 1.27 g(97%).

¹H NMR (300 MHz, DMSO-d₆) δ 9.12 (s, 1H), 6.6-7.8 (br, 2H), 6.99-7.13(m, 3H), 4.08 (m, 1H), 2.73-2.92 (m, 4H), 1.84-1.92 (m, 1H), 1.60-1.68(m, 1H). MS (ESI⁺) m/z 337 (M+H).

Example 24B (1-Bromo-2,2-dimethoxyethyl)benzene

(1-Bromo-2,2-dimethoxyethyl)benzene was synthesized according to theprocedure of Rasmussen and Bowadt (Synthesis 1989, 114). A solution ofphenylacetaldehyde (60 g, 500 mmol) in 250 mL MeOH was treated with 12.5g of activated 3 Å molecular sieves and was then brought to reflux withmechanical stirring. Bromine (25.6 mL, 500 mmol) was added dropwise. Themixture was refluxed for 5 hours, cooled to ambient temperature, andthen treated with potassium carbonate (35.4 g, 257 mmol). Stirring wascontinued for 1 hour after which the solids were filtered off. Thefiltrate was treated with brine (250 mL), and extracted with pentane(150 mL). Evaporation of the solvent afforded the title compound as abrown oil, 77.71 g (63%), which was used without further purification.

Example 24C8-(5-Phenylthiazol-2-ylamino)-1,2,3,4-tetrahydronaphthalen-2-ol

A mixture of the product of Example 24A (200 mg, 0.594 mmol) and theproduct of Example 24B (146 mg, 0.596 mmol) was refluxed for 2 hours ina mixture of EtOH (6 mL) and 1N HCl (1 mL). After cooling to roomtemperature, the mixture was quenched with saturated NaHCO₃ solution andwas extracted with EtOAc. The extracts were dried over Na₂SO₄, filteredevaporated under reduced pressure, and chromatographed on silica gel(95:5 to 92:8 CH₂Cl₂:CH₃OH eluant). The title compound was afforded as apale tan solid, 53 mg (28%). ¹H NMR (DMSO-d₆) δ 9.29 (s, 1H), 7.57 (m,2H), 7.46-7.49 (m, 2H), 7.33-7.38 (m, 2H), 7.22 (m, 1H), 7.10 (m, 1H),6.88 (d, J=7.4 Hz, 1H), 4.82 (d, J=4.0 Hz, 1H), 3.82 (m, 1H), 2.71-2.98(m, 4H), 1.83-1.93 (m, 1H), 1.57-1.66 (m, 1H). MS (ESI⁺) m/z 323 (M+H).Anal. calcd. For C₁₉H₁₈N₂OS: C, 70.78; H, 5.63; N, 8.69. Found: C,70.91; H, 5.37; N, 8.33.

Biological Activity

In Vitro Data—Determination of Inhibition Potencies

Dulbecco's modified Eagle medium (D-MEM)(with 4.5 mg/mL glucose) andfetal bovine serum were obtained from Hyclone Laboratories, Inc. (Logan,Utah). Dulbecco's phosphate-buffered saline (D-PBS)(with 1 mg/mL glucoseand 3.6 mg/l Na pyruvate)(without phenol red), L-glutamine, hygromycinB, and Lipofectamine™ were obtained from Life Technologies (GrandIsland, N.Y.). G418 sulfate was obtained from Calbiochem-NovabiochemCorp. (San Diego, Calif.). Capsaicin (8-methyl-N-vanillyl-6-nonenamide)was obtained from Sigma-Aldrich, Co. (St. Louis, Mo.). Fluo-4 AM(N-[4-[6-[(acetyloxy)methoxy]-2,7-difluoro-3-oxo-3H-xanthen-9-yl]-2-[2-[2-[bis[2-[(acetyloxy)methoxy]-2-oxyethyl]amino]-5-methylphenoxy]ethoxy]phenyl]-N-[2-[(acetyloxy)methoxy]-2-oxyethyl]-glycine,(acetyloxy)methyl ester) was purchased from Molecular Probes (Eugene,Oreg.).

The cDNAs for the human VR1 receptor were isolated by reversetranscriptase-polymerase chain reaction (RT-PCR) from human smallintestine poly A+RNA supplied by Clontech (Palo Alto, Calif.) usingprimers designed surrounding the initiation and termination codonsidentical to the published sequences (Hayes et al. Pain 88: 205-215,2000). The resulting cDNA PCR products were subcloned into pCIneomammalian expression vector (Promega) and fully sequenced usingfluorescent dye-terminator reagents (Prism, Perkin-Elmer AppliedBiosystems Division) and a Perkin-Elmer Applied Biosystems Model 373 DNAsequencer or Model 310 genetic analyzer. Expression plasmids encodingthe hVR1 cDNA were transfected individually into 1321N1 humanastrocytoma cells using Lipofectamine™. Forty-eight hours aftertransfection, the neomycin-resistant cells were selected with growthmedium containing 800 μg/mL Geneticin (Gibco BRL). Surviving individualcolonies were isolated and screened for VR1 receptor activity. Cellsexpressing recombinant homomeric VR1 receptors were maintained at 37° C.in D-MEM containing 4 mM L-glutamine, 300 μg/mL G418 (Cal-biochem) and10% fetal bovine serum under a humidified 5% CO₂ atmosphere.

The functional activity of compounds at the VR1 receptor was determinedwith a Ca²⁺ influx assay and measurement of intracellular Ca²⁺ levels([Ca²⁺]i). All compounds were tested over an 11-point half-logconcentration range. Compound solutions were prepared in D-PBS (4× finalconcentration), and diluted serially across 96-well v-bottom tissueculture plates using a Biomek 2000 robotic automation workstation(Beckman-Coulter, Inc., Fullerton, Calif.). A 0.2 μM solution of the VR1agonist capsaicin was also prepared in D-PBS. The fluorescent Ca²⁺chelating dye fluo-4 was used as an indicator of the relative levels of[Ca²⁺]i in a 96-well format using a Fluorescence Imaging Plate Reader(FLIPR)(Molecular Devices, Sunnyvale, Calif.). Cells were grown toconfluency in 96-well black-walled tissue culture plates. Then, prior tothe assay, the cells were loaded with 100 μL per well of fluo-4 AM (2μM, in D-PBS) for 1-2 hours at 23° C. Washing of the cells was performedto remove extracellular fluo-4 AM (2×1 mL D-PBS per well), andafterward, the cells were placed in the reading chamber of the FLIPRinstrument. 50 μL of the compound solutions were added to the cells atthe 10 second time mark of the experimental run. Then, after a 3 minutetime delay, 50 μL of the capsaicin solution was added at the 190 secondtime mark (0.05 μM final concentration)(final volume=200 μL) tochallenge the VR1 receptor. Time length of the experimental run was 240seconds. Fluorescence readings were made at 1 to 5 second intervals overthe course of the experimental run. The peak increase in relativefluorescence units (minus baseline) was calculated from the 190 secondtime mark to the end of the experimental run, and expressed as apercentage of the 0.05 μM capsaicin (control) response. Curve-fits ofthe data were solved using a four-parameter logistic Hill equation inGraphPad Prism® (GraphPad Software, Inc., San Diego, Calif.), andIC_(so) values were calculated.

The compounds of the present invention were found to be antagonists ofthe vanilloid receptor subtype 1 (VR1) receptor with IC_(50s) lower than12 μM, preferably lower than 5 μM, more preferably less than 1 μM, andmost preferably less than 0.1 μM.

In Vivo Data—Determination of Antinociceptive Effect

Experiments were performed on 400 adult male 129J mice (JacksonLaboratories, Bar Harbor, Me.), weighing 20-25 g. Mice were kept in avivarium, maintained at 22° C., with a 12 hour alternating light-darkcycle with food and water available ad libitum. All experiments wereperformed during the light cycle. Animals were randomly divided intoseparate groups of 10 mice each. Each animal was used in one experimentonly and was sacrificed immediately following the completion of theexperiment. All animal handling and experimental procedures wereapproved by an IACUC Committee. The Complete Freund's Adjuvant-inducedThermal Hyperalgesia (CFA) assay described in Pircio et al. Eur J.Pharmacol. Vol. 31(2) pages 207-215 (1975). Chronic inflammatoryhyperalgesia was induced in one group of rats following the injection ofcomplete Freund's adjuvant (CFA, 50%, 150 μL) into the plantar surfaceof the right hindpaw 48 hours prior to testing. Thermal nociceptivethresholds were measured in three different groups of rats. The ED_(50s)were determined based on the oral administration.

The in vitro and in vivo data demonstrates that compounds of the presentinvention antagonize the VR1 receptor and are useful for treating pain,bladder overactivity, and urinary incontinence.

1. A compound of formula (I)

or a pharmaceutically acceptable salt, amide, ester, prodrug, or salt ofa prodrug thereof, wherein A is O or —N(R₃); D is —N(R₄), O or S; R₃ andR₄ are each independently selected from the group consisting ofhydrogen, alkyl, —C(O)alkyl, and —S(O)₂(alkyl); R₁ and R₂ are eachindependently selected from the group consisting of hydrogen, alkyl,alkenyl, cyano, nitro, halogen, —OR₅, —OC(O)R₅, —SR₅, —S(O)₂R₅,—S(O)₂OR₅, —S(O)₂N(R₅)(R₆), —N(R₅)(R₆), —N(R₆)C(O)R₅,—N(R₆)C(O)N(R₅)(R₆), —N(R₆)S(O)₂N(R₅)(R₆), —C(O)R₅, —C(O)OR₅,—C(O)N(R₅)(R₆), haloalkyl, -alkylenyl-OR₅, -alkylenyl-OC(O)R₅,-alkylenyl-SR₅, -alkylenyl-S(O)₂R₅, -alkylenyl-S(O)₂OR₅,-alkylenyl-S(O)₂N(R₅)(R₆), -alkylenyl-N(R₅)(R₆), -alkylenyl-N(R₆)C(O)R₅,-alkylenyl-N(R₆)C(O)N(R₅)(R₆), -alkylenyl-N(R₆)S(O)₂N(R₅)(R₆),-alkylenyl-C(O)R₅, -alkylenyl-C(O)OR₅, -alkylenyl-C(O)N(R₅)(R₆), —R₇,and -alkylenyl-R₇; provided that when one of R₁ and R₂ is hydrogen, theother is not hydrogen; R₅ at each occurrence is independently selectedfrom the group consisting of hydrogen, alkyl, alkenyl, haloalkyl andbenzyl; R₆ at each occurrence is independently selected from the groupconsisting of hydrogen and alkyl; R₇ at each occurrence is independentlyselected from the group consisting of cycloalkyl, cycloalkenyl,heterocycle, aryl and heteroaryl; wherein each R₇ is independentlysubstituted with 0, 1, 2, 3, 4 or 5 substituents independently selectedfrom the group consisting of alkyl, alkenyl, halogen, cyano, nitro,hydroxy, alkoxy, haloalkoxy, —S(alkyl), —S(O)₂(alkyl), —N(H)₂,—N(H)(alkyl), —N(alkyl)₂, —N(H)C(O)alkyl, —C(O)OH, —C(O)Oalkyl,—C(O)NH₂, —C(O)N(H)alkyl, —C(O)N(alkyl)₂, —R₈, cyanoalkyl, haloalkyl,hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, -alkylenyl-S(alkyl),-alkylenyl-S(O)₂(alkyl), -alkylenyl-N(H)₂, -alkylenyl-N(H)(alkyl),-alkylenyl-N(alkyl)₂, -alkylenyl-N(H)C(O)alkyl, -alkylenyl-C(O)OH,-alkylenyl-C(O)Oalkyl, -alkylenyl-C(O)NH₂, -alkylenyl-C(O)N(H)alkyl,-alkylenyl-C(O)N(alkyl)₂, and -alkylenyl-R₈; R₈ at each occurrence isindependently selected from the group consisting of cycloalkyl,cycloalkenyl, heterocycle, aryl and heteroaryl; wherein each R₈ isindependently substituted with 0, 1, 2, 3, 4 or 5 substituentsindependently selected from the group consisting of alkyl, alkenyl,halogen, cyano, nitro, hydroxy, alkoxy, haloalkoxy, —S(alkyl),—S(O)₂(alkyl), —N(H)₂, —N(H)(alkyl), —N(alkyl)₂, —N(H)C(O)alkyl,—C(O)OH, —C(O)Oalkyl, —C(O)NH₂, —C(O)N(H)alkyl, —C(O)N(alkyl)₂,cyanoalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl,-alkylenyl-S(alkyl), -alkylenyl-S(O)₂(alkyl), -alkylenyl-N(H)₂,-alkylenyl-N(H)(alkyl), -alkylenyl-N(alkyl)₂, -alkylenyl-N(H)C(O)alkyl,-alkylenyl-C(O)OH, -alkylenyl-C(O)Oalkyl, -alkylenyl-C(O)NH₂,-alkylenyl-C(O)N(H)alkyl, and -alkylenyl-C(O)N(alkyl)₂; W and Y are eachindependently selected from the group consisting of —C(R_(x))(R_(y))—and —N(R_(z))—; provided that when one of W and Y is —N(R_(z))—, thenthe other is —C(R_(x))(R_(y))—; X is selected from the group consistingof —C(O)—, —C(R_(x))(R_(y))—, —N(R_(z)),—C(R_(x))(R_(y))—C(R_(x))(R_(y))—, —C(O)—C(R_(x))(R_(y))—,—C(R_(x))(R_(y))—C(O)—, —C(R_(x))(R_(y))—N(R_(z))— and—N(R_(z))—C(R_(x))(R_(y))—; provide that when one of W and Y is—N(R_(z))—, then X is selected from the group consisting of—C(R_(x))(R_(y))— and —C(R_(x))(R₃₇)—C(R_(x))(R_(y))—; R_(x) and R_(y)at each occurrence are each independently selected from the groupconsisting of hydrogen, alkyl, haloalkyl, —OR_(a), —OC(O)R_(a), —SR_(a),—S(O)₂R_(a), —S(O)₂N(R_(a))(R_(b)), —S(O)₂OR_(a), —N(R_(a))(R_(b)),—N(R_(b))C(O)R_(a), —N(R_(b))C(O)N(R_(a))(R_(b)),—N(R_(b))S(O)₂N(R_(a))(R_(b)), —C(O)OR_(a), —C(O)R_(a),—C(O)N(R_(a))(R_(b)), -alkylenyl-OR_(a), -alkylenyl-OC(O)R_(a),-alkylenyl-SR_(a), -alkylenyl-S(O)₂R_(a),-alkylenyl-S(O)₂N(R_(a))(R_(b)), -alkylenyl-S(O)₂OR_(a),-alkylenyl-N(R_(a))(R_(b)), -alkylenyl-N(R_(b))C(O)R_(a),-alkylenyl-N(R_(b))C(O)N(R_(a))(R_(b)),-alkylenyl-N(R_(b))S(O)₂N(R_(a))(R_(b)), -alkylenyl-C(O)OR_(a),-alkylenyl-C(O)R_(a), -alkylenyl-C(O)N(R_(a))(R_(b)), —R₈ and-alkylenyl-R₈; R_(a) at each occurrence is independently selected fromthe group consisting of hydrogen, alkyl, haloalkyl, —R₈ and-alkylenyl-R₈; R_(b) at each occurrence is independently selected fromthe group consisting of hydrogen, alkyl and haloalkyl; alternatively,R_(a) and R_(b) together with the nitrogen atom to which they areattached form a heterocycle ring substituted with 0, 1, 2, 3, 4 or 5substituents independently selected from the group consisting ofhalogen, alkyl and haloalkyl; R_(z) at each occurrence is independentlyselected from the group consisting of hydrogen, alkyl, —C(O)alkyl, and—S(O)₂(alkyl); R₉ at each occurrence is independently selected from thegroup consisting of halogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyland haloalkoxyalkyl; and n is 0, 1, 2, or
 3. 2. The compound of formula(I) according to claim 1, wherein D is —N(R₄).
 3. The compound accordingto claim 2, wherein A is O.
 4. The compound according to claim 2,wherein A is —N(R₃).
 5. The compound of formula (I) according to claim1, wherein D is S.
 6. The compound according to claim 5, wherein A is O.7. The compound according to claim 5, wherein A is —N(R₃).
 8. Thecompound of formula (I) according to claim 1, wherein D is O.
 9. Thecompound of formula (I) according to claim 8, wherein A is O.
 10. Thecompound according to claim 8, wherein A is —N(R₃).
 11. The compoundaccording to claim 10, wherein R₃ is hydrogen.
 12. The compoundaccording to claim 11, wherein R₂ is —R₇ and R₁ is hydrogen.
 13. Thecompound according to claim 12, wherein —R₇ is aryl.
 14. The compoundaccording to claim 13, wherein —R₇ is phenyl.
 15. The compound accordingto claim 14, wherein W is —C(R_(x))(R_(y)); Y is —C(R_(x))(R_(y)); and Xis —C(O)—C(R_(x))(R_(y))—.
 16. The compound according to claim 15,wherein R_(x) and R_(y) are hydrogen.
 17. The compound according toclaim 16, wherein the compound is selected from the group consisting of:8-({5-[4-(trifluoromethyl)phenyl]-1,3-oxazol-2-yl}amino)-3,4-dihydronaphthalen-2(1H)-one;8-{[5-(4-tert-butylphenyl)-1,3-oxazol-2-yl]amino}-3,4-dihydronaphthalen-2(1H)-one;8-{[5-(4-chlorophenyl)-1,3-oxazol-2-yl]amino}-3,4-dihydronaphthalen-2(1H)-one;8-{[5-(4-bromophenyl)-1,3-oxazol-2-yl]amino}-3,4-dihydronaphthalen-2(1H)-one;8-{[5-(4-methoxyphenyl)-1,3-oxazol-2-yl]amino}-3,4-dihydronaphthalen-2(1H)-one;8-[(5-phenyl-1,3-oxazol-2-yl)-amino]-3,4-dihydronaphthalen-2(1H)-one;8-{[5-(2-methylphenyl)-1,3-oxazol-2-yl]amino}-3,4-dihydronaphthalen-2(1H)-one;and8-{[5-(3-methylphenyl)-1,3-oxazol-2-yl]amino}-3,4-dihydronaphthalen-2(1H)-one.18. The compound according to claim 14, wherein W is —C(R_(x))(R_(y)); Yis —C(R_(x))(R_(y)); and X is —C(R_(x))(R_(y))—C(R_(x))(R_(y))—.
 19. Thecompound according to claim 18 wherein R_(x) is —N(R_(a))(R_(b)), andR_(a) and R_(b) are hydrogen.
 20. The compound according to claim 19,wherein the compound is selected from the group consisting of:N¹-(5-p-methylphenyloxazol-2-O-5,6,7,8-tetrahydronaphthalene-1,7-diamine;N¹-[5-(4-Trifluoromethylphenyl)oxazol-2-yl]-5,6,7,8-tetrahydronaphthalene-1,7-diamine;andN¹-[5-(2-Fluoro-4-trifluoromethylphenyl)oxazol-2-yl]-5,6,7,8-tetrahydro-naphthalene-1,7-diamine.21. The compound according to claim 18, wherein R_(x) is selected fromthe group consisting of hydrogen and —O(R_(a)), wherein R_(y) ishydrogen, and wherein R_(a) is hydrogen.
 22. The compound according toclaim 21, wherein the compound is selected from the group consisting of:8-({5-[4-(trifluoromethyl)phenyl]-1,3-oxazol-2-yl}amino)-1,2,3,4-tetrahydronaphthalen-2-ol;8-{[5-(4-tert-butylphenyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-ol;(2S)-8-{[5-(4-tert-butylphenyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-ol;(2R)-8-{[5-(4-tert-butylphenyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-ol;8-{[5-(4-chlorophenyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-ol;8-{[5-(4-pyrrolidin-1-ylphenyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-ol;8-{[5-(4-bromophenyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-ol;8-{[5-(4-methylphenyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-ol;8-{[5-(4-methoxyphenyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-ol;8-[(5-phenyl-1,3-oxazol-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-2-ol;8-{[5-(2-methylphenyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-ol;and8-{[5-(3-methylphenyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-ol.23. The compound according to claim 18, wherein R_(x) is—N(R_(a))(R_(b)), R_(a) is —S(O)₂(alkyl), and R_(b) is hydrogen.
 24. Thecompound of claim 23 that isN-[8-(5-p-methylphenyloxazol-2-ylamino)-1,2,3,4-tetrahydronaphthalen-2-yl]methanesulfonamide.25. The compound according to claim 12, wherein —R₇ is cycloalkyl. 26.The compound according to claim 25, wherein W is —C(R_(x))(R_(y)); Y is—C(R_(x))(R_(y)); and X is —C(O)—C(R_(x))(R_(y))—.
 27. The compoundaccording to claim 26, wherein R_(x) and R_(y) are hydrogen.
 28. Thecompound according to claim 27, that is8-{[5-(1-adamantyl)-1,3-oxazol-2-yl]amino}-3,4-dihydronaphthalen-2(1H)-one.29. The compound according to claim 25, wherein W is —C(R_(x))(R_(y)); Yis —C(R_(x))(R_(y)); and X is —C(R_(x))(R_(y))—C(R_(x))(R_(y))—.
 30. Thecompound according to claim 29, wherein R_(x) is selected from the groupconsisting of hydrogen and —O(R_(a)), wherein R_(a) is hydrogen, andwherein R_(y) is hydrogen.
 31. The compound according to claim 30, thatis8-{[5-(1-adamantyl)-1,3-oxazol-2-yl]amino}-1,2,3,4-tetrahydronaphthalen-2-ol.32. The compound according to claim 11, wherein R₂ is alkyl and R₁ ishydrogen.
 33. The compound according to claim 32, wherein W is—C(R_(x))(R_(y)); Y is —C(R_(x))(R_(y)); and X is—C(O)—C(R_(x))(R_(y))—; and wherein R_(x) and R_(y) are hydrogen. 34.The compound according to claim 33, wherein the compound is selectedform the group consisting of:8-[(5-methyl-1,3-oxazol-2-yl)-amino]-3,4-dihydronaphthalen-2 (1H)-one;and8-[(5-tert-butyl-1,3-oxazol-2-yl)-amino]-3,4-dihydronaphthalen-2(1H)-one.35. The compound according to claim 32, wherein W is —C(R_(x))(R_(y)); Yis —C(R_(x))(R_(y)); and X is —C(R_(x))(R_(y))—C(R_(x))(R_(y))—; whereinR_(x) is selected from the group consisting of hydrogen and —O(R_(a)),wherein R_(a) is hydrogen and wherein R_(y) is hydrogen.
 36. Thecompound according to claim 35, that is8-[(5-methyl-1,3-oxazol-2-yl)-amino]-1,2,3,4-tetrahydronaphthalen-2-ol;and8-[(5-tert-butyl-1,3-oxazol-2-yl)-amino]-1,2,3,4-tetrahydronaphthalen-2-ol.37. The compound according to claim 11, wherein R₂ is -alkyl-R₇ and R₁is hydrogen.
 38. The compound according to claim 37, wherein R₇ isphenyl.
 39. The compound according to claim 38, wherein W is—C(R_(x))(R_(y)); Y is —C(R_(x))(R_(y)); X is —C(O)—C(R_(x))(R_(y))—;and wherein R_(x) and R_(y) are hydrogen.
 40. The compound of claim 39that is8-[(5-benzyl-1,3-oxazol-2-yl)amino]-3,4-dihydronaphthalen-2(1H)-one. 41.The compound according to claim 38, wherein W is —C(R_(x))(R_(y)); Y is—C(R_(x))(R_(y)); X is —C(R_(x))(R_(y))—C(R_(x))(R_(y))—; wherein R_(x)is selected from the group consisting of hydrogen and —O(R_(a)), whereinR_(a) is hydrogen and wherein R_(y) is hydrogen.
 42. The compoundaccording to claim 41, wherein the compound is8-[(5-benzyl-1,3-oxazol-2-yl)amino]-1,2,3,4-tetrahydronaphthalen-2-ol.43. The compound according to claim 10, wherein R₃ is alkyl; W is—C(R_(x))(R_(y)); Y is —C(R_(x))(R_(y)); X is—C(R_(x))(R_(y))—C(R_(x))(R_(y))—; R_(x) is selected from the groupconsisting of hydrogen and —O(R_(a)), wherein R_(a) is hydrogen andwherein R_(y) is hydrogen.
 44. The compound according to claim 43,wherein the compound is 8-(methyl{5-[4-(trifluoromethyl)phenyl]-1,3-oxazol-2-yl}amino)-1,2,3,4-tetrahydronaphthalen-2-ol.45. The compound according to claim 10, wherein R₃ is alkyl; W is—C(R_(x))(R_(y)); Y is —C(R_(x))(R_(y)); and X is—C(O)—C(R_(x))(R_(y))—.
 46. The compound according to claim 10, whereinR₃ is —C(O)alkyl; W is —C(R_(x))(R_(y)); Y is —C(R_(x))(R_(y)); X is—C(R_(x))(R_(y))—C(R_(x))(R_(y))—; R_(x) is selected from the groupconsisting of hydrogen and —O(R_(a)), wherein R_(a) is hydrogen andwherein R_(y) is hydrogen.
 47. The compound according to claim 46,wherein the compound isN-[5-(4-tert-butylphenyl)-1,3-oxazol-2-yl]-N-(7-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)acetamide.48. The compound according to claim 10, wherein R₃ is —C(O)alkyl; W is—C(R_(x))(R_(y)); Y is —C(R_(x))(R_(y)); and X is—C(O)—C(R_(x))(R_(y))—.
 49. The compound according to claim 7, whereinR₁ is hydrogen; R₂ is —R₇, R₃ is hydrogen; R₇ is phenyl; W is—C(R_(x))(R_(y)); Y is —C(R_(x))(R_(y)); X is—C(R_(x))(R_(y))—C(R_(x))(R_(y))—; R_(x) is —O(R_(a)), and R_(y) ishydrogen.
 50. The compound according to claim 49, wherein the compoundis: 8-(5-Phenylthiazol-2-ylamino)-1,2,3,4-tetrahydronaphthalen-2-ol. 51.A pharmaceutical composition comprising a therapeutically effectiveamount of a compound of formula (I) according to claim 1, or apharmaceutically acceptable salt, ester, amide, or prodrug thereof. 52.A method of treating a disorder wherein the disorder is ameliorated byinhibiting vanilloid receptor subtype 1 (VR1) in a host mammal in needof such treatment comprising administering a therapeutically effectiveamount of a compound of formula (I) according to claim 1, or apharmaceutically acceptable salt thereof.
 53. The method of claim 52,wherein the disorder is selected from the group of pain, neuropathicpain, allodynia, pain associated with inflammation, inflammatoryhyperalgesia, bladder overactivity, and urinary incontinence.
 54. Amethod of treating bladder overactivity in a host mammal in need of suchtreatment comprising administering a therapeutically effective amount ofa compound of formula (I) according to claim 1, or a pharmaceuticallyacceptable salt thereof.
 55. A method of treating urinary incontinencein a host mammal in need of such treatment comprising administering atherapeutically effective amount of a compound of formula (I) accordingto claim 1, or a pharmaceutically acceptable salt thereof.
 56. A methodof treating pain in a host mammal in need of such treatment comprisingadministering a therapeutically effective amount of a compound offormula (I) according to claim 1, or a pharmaceutically acceptable saltthereof.
 57. A method of treating thermal hyperalgesia in a host mammalin need of such treatment comprising administering a therapeuticallyeffective amount of a compound of formula (I) according to claim 1, or apharmaceutically acceptable salt thereof.